Tag: NOVEL

  • BPN14770

    First-in-class allosteric inhibitor of phosphodiesterase-4D (PDE4D) with subtype selectivity and primate-specific potency enhancement

    A PDE4D-selective allosteric inhibitor developed by Tetra Therapeutics (Shionogi) that enhances cAMP-PKA-CREB signaling to promote memory consolidation, synaptic plasticity, and neuroprotection, distinguished from classical PDE4 inhibitors by subtype selectivity and a wide therapeutic window separating cognitive benefit from emetic side effects.

    Abstract

    BPN14770 (zatolmilast) is a first-in-class, subtype-selective, allosteric inhibitor of phosphodiesterase-4D (PDE4D) that was discovered at Tetra Discovery Partners (later Tetra Therapeutics) and is currently in late-stage clinical development under Shionogi, which acquired Tetra in May 2020. The compound is distinguished from the two approved PDE4 inhibitors (roflumilast and apremilast) and from the classical PDE4 research tool rolipram by three principal features: allosteric rather than competitive inhibition of the PDE4D catalytic site, high selectivity for the PDE4D subtype over PDE4A, PDE4B, and PDE4C (approximately 730-fold selectivity over PDE4B), and exploitation of a primate-specific amino acid residue in the PDE4D N-terminal regulatory domain (UCR2 helix) that confers approximately 100-fold greater potency in humanized transgenic mice relative to wild-type mice, while simultaneously producing low potency in the xylazine/ketamine emesis surrogate assay. These properties yield a therapeutic index of 40- to 100-fold between plasma exposures that produce cognitive and neurochemical benefit (10 to 30 ng/mL) and those projected to cause emesis in non-rodent species (approximately 1,300 ng/mL), a margin that has historically been the dose-limiting constraint for PDE4 inhibitors in cognitive indications.

    The molecular pharmacology of BPN14770 is centered on the cAMP-PKA-CREB signaling cascade. Inhibition of PDE4D elevates intracellular cyclic adenosine monophosphate (cAMP) in hippocampal and cortical neurons, activating protein kinase A (PKA), which phosphorylates the transcription factor CREB (cAMP response element-binding protein). Phosphorylated CREB drives expression of brain-derived neurotrophic factor (BDNF), synapsin, postsynaptic density protein 95 (PSD-95), and other effectors of synaptic plasticity and memory consolidation. In humanized PDE4D mice, a single acute oral dose of BPN14770 at 0.01 mg/kg elevated hippocampal cAMP nearly threefold, augmented the late phase of long-term potentiation (LTP), reversed scopolamine-induced impairment of short-term memory, and improved long-term memory through a PKA-dependent mechanism confirmed by the PKA inhibitor H-89. Repeated dosing for 14 days at 0.03 mg/kg elevated hippocampal BDNF 2.1-fold and phospho-CREB 2.3-fold. In an amyloid-beta neurotoxicity model, 14-day oral BPN14770 at 0.01 to 0.03 mg/kg protected hippocampal pyramidal neurons from dendritic atrophy, preserved spine density, restored pCREB/CREB and BDNF/VGF ratios, and normalized spatial and working memory. A separate pathway analysis confirmed that BPN14770 engages the cAMP-PKA-SIRT1-Akt-Bcl-2/Bax signaling module, producing neuroprotective and anti-apoptotic effects.

    Clinically, BPN14770 has been evaluated in two Phase 1 trials in 109 healthy adults (single doses up to 100 mg, multiple doses of 10 to 40 mg twice daily in elderly volunteers), a Phase 2 PICASSO trial in 255 patients with early Alzheimer’s disease (10 or 25 mg twice daily for 12 weeks), and a Phase 2 crossover trial in 30 adult males with Fragile X syndrome (25 mg twice daily for 12 weeks). The Phase 1 trials established linear pharmacokinetics, oral bioavailability of 70 to 80 percent, a plasma half-life of 8 to 10 hours, and a brain-to-plasma ratio of approximately 0.4. The PICASSO Alzheimer’s trial missed its primary endpoint (RBANS Delayed Memory Index) but showed a signal on the Clinical Dementia Rating Sum of Boxes (CDR-SB) in a higher-dose subgroup. The Fragile X Phase 2 trial met its primary endpoint of safety and tolerability and demonstrated significant improvement on NIH Toolbox Oral Reading Recognition, Picture Vocabulary, and Cognition Crystallized Composite Score, with clinically significant caregiver-rated improvement in language and daily functioning. Shionogi subsequently initiated the EXPERIENCE Phase 2b/3 program comprising three studies (EXPERIENCE-204 in adolescents, EXPERIENCE-301 in adults, EXPERIENCE-302 open-label extension) for Fragile X syndrome. Topline results from the Phase 3 trials indicated that neither study met its originally specified primary endpoint of cognitive improvement on the NIH Toolbox, though the adult study (EXPERIENCE-301) showed statistically significant improvement on the caregiver-assessed Numeric Rating Scale. The compound holds FDA Fast Track designation, Orphan Drug designation in both the United States and European Union, and Rare Pediatric Disease designation for Jordan’s syndrome (Houge-Janssens syndrome 1), for which a Phase 2 trial enrolling 30 participants was initiated in February 2025.

    The compound is well tolerated in clinical studies. The most common adverse events are headache, transient nausea, and vomiting, occurring at rates modestly above placebo. No serious adverse events attributable to the compound have been reported. The favorable emetic profile relative to classical PDE4 inhibitors reflects the allosteric mechanism and PDE4D subtype selectivity, which avoid the PDE4B-mediated emesis that limits rolipram and constrains roflumilast dosing.

    This monograph reviews the chemistry, structural pharmacology, and primate-specific binding of BPN14770; the cAMP-PKA-CREB-BDNF signaling mechanism in molecular detail; the comprehensive preclinical pharmacology across scopolamine, amyloid-beta, and Fragile X models; human pharmacokinetics; the clinical evidence base in Alzheimer’s disease, Fragile X syndrome, and Jordan’s syndrome; sourcing and quality verification for research applications; reconstitution and handling; stack-interaction considerations; adverse-event signal; and a structured comparative assessment of five PDE4 inhibitor candidates (roflumilast, apremilast, rolipram, MK-0952, GEBR-7b) against BPN14770 on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • UBX1325

    Senolytic Bcl-xL inhibitor (phosphate prodrug); small-molecule inducer of apoptosis in senescent retinal vascular endothelial cells

    A first-in-class senolytic Bcl-xL inhibitor developed by Unity Biotechnology as an intravitreal therapy for diabetic macular edema and age-related macular degeneration, distinguished from conventional anti-VEGF agents by its mechanism of selective elimination of senescent retinal vascular cells and its potential for durable, disease-modifying efficacy from infrequent dosing.

    Abstract

    UBX1325 (foselutoclax) is a soluble phosphate prodrug that is cleaved rapidly in ocular tissues by ubiquitous phosphatases to yield the active parent molecule UBX0601, a potent inhibitor of the B-cell lymphoma-extra large (Bcl-xL) anti-apoptotic protein and related Bcl-2 family members. The compound was developed by Unity Biotechnology as the first senolytic therapeutic candidate designed for intravitreal administration in ophthalmologic indications, principally diabetic macular edema (DME), diabetic retinopathy (DR), and neovascular (wet) age-related macular degeneration (AMD). The senolytic mechanism is fundamentally distinct from the anti-vascular endothelial growth factor (anti-VEGF) agents that constitute the current standard of care for these conditions: rather than neutralizing a single cytokine to reduce vascular permeability, UBX1325 selectively induces apoptosis in senescent retinal vascular endothelial cells that have accumulated in areas of disease activity, thereby removing a persistent source of pro-inflammatory and pro-permeability signaling and potentially modifying the underlying disease process rather than managing its downstream consequences.

    The compound originated from a 2016 strategic licensing arrangement between Unity Biotechnology and Ascentage Pharma, under which Unity screened Ascentage’s Bcl-2 family compound library for candidates with senolytic activity against age-related disease targets. The selected molecule, BM-962, was optimized as a phosphate prodrug (UBX1325/foselutoclax) to improve aqueous solubility for ophthalmic formulation. Preclinical studies demonstrated that intravitreal administration of UBX1325 in oxygen-induced retinopathy and streptozotocin-induced diabetic retinopathy mouse models selectively eliminated senescent cells from diseased retinal vasculature while sparing healthy tissue, reduced retinal vascular permeability, and improved retinal function as measured by electroretinography. A Phase 1 single ascending dose study in 12 patients with advanced DME and wet AMD (NCT04537884) established safety and tolerability at doses up to 10 micrograms, with no dose-limiting toxicities, no treatment-related serious adverse events, and encouraging signals of visual acuity improvement and retinal thickness reduction persisting through 12 weeks. The Phase 2 BEHOLD trial (NCT04857996) enrolled 65 patients with DME who had suboptimal response to prior anti-VEGF therapy and randomized them to a single intravitreal injection of 10 micrograms UBX1325 or sham; at 48 weeks, UBX1325-treated patients gained a mean of 6.2 ETDRS letters from baseline (5.6 letters over sham), with 53 percent of treated patients requiring no anti-VEGF rescue through the full study duration compared to 22 percent in the sham arm. These results, published in Nature Medicine in 2024, represent the first clinical demonstration of senolytic therapy in ophthalmology. The Phase 2 ENVISION trial (NCT05275205) in wet AMD did not meet its primary non-inferiority endpoint versus aflibercept at 24 weeks, though 40 percent of UBX1325-treated patients required no anti-VEGF rescue through 48 weeks. The Phase 2b ASPIRE trial (NCT06011798) evaluated repeat dosing of UBX1325 every 8 weeks versus aflibercept every 8 weeks in 52 DME patients; at 36 weeks, UBX1325 produced mean gains of 5.5 ETDRS letters, achieving non-inferiority to aflibercept at most time points except the pre-specified primary endpoint (average of weeks 20 and 24), with superior performance in a pre-specified subgroup of patients with baseline central subfield thickness below 400 microns.

    This monograph reviews the chemistry, prodrug design, and molecular pharmacology of UBX1325; the senolytic mechanism of action through Bcl-xL inhibition; the preclinical pharmacology in retinal disease models; the complete clinical evidence base across Phase 1, BEHOLD, ENVISION, and ASPIRE trials; reconstitution and handling considerations for intravitreal formulation; stack interactions with anti-VEGF agents and corticosteroids; the adverse-event and safety profile; and a structured comparative assessment of five alternative approaches to DME therapy (aflibercept, faricimab, ranibizumab, navitoclax, and dasatinib plus quercetin) against UBX1325 on five competency standards. The compound is not approved by any regulatory authority as of the monograph revision date. Unity Biotechnology is advancing development toward registrational trials.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • 78c

    Thiazoloquin(az)olin(on)e small-molecule CD38 NADase inhibitor

    A potent, specific, reversible, and uncompetitive small-molecule inhibitor of the NAD+ glycohydrolase CD38, developed from a thiazoloquinolin(on)e medicinal chemistry series and distinguished by low-nanomolar potency, oral bioavailability, and demonstrated reversal of age-related tissue NAD+ decline with extension of lifespan and healthspan in murine aging models.

    Abstract

    Compound 78c (CD38-IN-78c; CAS 1700637-55-3) is a thiazoloquinolin(on)e small molecule identified as the lead compound from a structure-activity exploration of CD38 inhibitors reported by Haffner, Bhatt, and colleagues in 2015. It is a potent, specific, reversible, and uncompetitive inhibitor of the ectoenzyme CD38 (cluster of differentiation 38), a type II transmembrane glycoprotein with NAD+ glycohydrolase, ADP-ribosyl cyclase, and cyclic ADP-ribose hydrolase activities, with half-maximal inhibitory concentration (IC50) values of 7.3 nM against human CD38 and 1.9 nM against murine CD38, and an inhibition constant (Ki) of 8.4 nM. The compound is cell-permeable, orally bioavailable in rodent species, and non-toxic at pharmacologically active doses in chronic administration studies extending to 20 months. CD38 has been identified as the principal enzyme responsible for age-related tissue NAD+ decline, a process that contributes to mitochondrial dysfunction, impaired sirtuin signaling, metabolic derangement, and the progressive physiological deterioration characteristic of aging. By inhibiting CD38-mediated degradation of NAD+ and its biosynthetic precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), compound 78c elevates tissue NAD+ levels (greater than 5-fold in liver and greater than 1.2-fold in skeletal muscle in diet-induced obese mice at a 2-hour time point) and thereby restores the activity of NAD+-dependent enzymes including sirtuins 1, 3, and 6 and poly(ADP-ribose) polymerases.

    The landmark 2018 publication by Tarrago, Chini, and colleagues in Cell Metabolism demonstrated that chronic oral administration of 78c to naturally aged mice and to Cockayne syndrome progeroid mice reverses age-related NAD+ decline and improves glucose tolerance, exercise capacity, muscle function, and cardiac function. A follow-up 2022 study by Peclat and colleagues in Aging Cell extended these findings to chronological aging, reporting that 78c increases median lifespan by approximately 10 percent, extends maximal lifespan, and improves multiple healthspan parameters including treadmill endurance, grip strength, body composition, and metabolic markers in naturally aged C57BL/6 mice, with sex-dependent differences in the magnitude of benefit. Additional preclinical studies have demonstrated cardioprotection against ischemia-reperfusion injury through preservation of tetrahydrobiopterin (BH4) and endothelial nitric oxide synthase coupling; anti-inflammatory activity through suppression of NF-kappaB-dependent cytokine expression (IL-1beta, IL-6, TNF-alpha) in macrophages and microglia; therapeutic efficacy in collagen-induced arthritis through restoration of regulatory T cell populations and immune balance; and attenuation of osteoclastogenesis and inflammatory bone resorption. The compound does not cross the blood-brain barrier at appreciable concentrations but exerts systemic anti-inflammatory and metabolic effects relevant to age-related neurodegeneration through peripheral NAD+ homeostasis.

    Compound 78c has not entered human clinical trials. It is supplied by multiple research chemical vendors at greater than 98 percent purity as a research tool compound. The current research state is one of strong and replicable preclinical efficacy across aging, cardiovascular, inflammatory, and metabolic disease models, with absent clinical pharmacokinetic and safety data in humans. This monograph reviews the chemistry, synthesis, and structure-activity relationships of 78c; the molecular pharmacology of CD38 inhibition and NAD+ metabolism; the preclinical pharmacokinetic profile; the preclinical efficacy data across aging, cardiovascular, inflammatory, and metabolic disease models; sourcing and quality considerations; reconstitution and handling; stack-interaction considerations with NAD+ precursors and other metabolic agents; adverse-event and safety signal from chronic animal dosing; and a comparative assessment of five alternative CD38-targeting or NAD+-elevating compounds (MK-0159, apigenin, luteolin, quercetin, and daratumumab) against 78c on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • AAZ-A-154

    Non-hallucinogenic psychoplastogen; isotryptamine-derived 5-HT2A receptor partial agonist with neuroplasticity-promoting activity

    A non-hallucinogenic isotryptamine psychoplastogen discovered via engineered 5-HT2A biosensor screening at UC Davis, producing rapid and sustained antidepressant-like effects through serotonin receptor-mediated structural neuroplasticity without psychedelic, dissociative, or psychotomimetic activity.

    Abstract

    AAZ-A-154, subsequently designated DLX-001 and assigned the international nonproprietary name zalsupindole, is a substituted isotryptamine derivative that acts as a low-potency, low-efficacy partial agonist of the serotonin 5-HT2A receptor (EC50 approximately 8,200 nM; Emax approximately 17 percent of serotonin maximum) and a moderate-efficacy partial agonist of the 5-HT2C receptor (EC50 approximately 3,300 nM; Emax approximately 70 percent), with silent antagonism at the 5-HT2B receptor and selectivity for serotonergic over dopaminergic, adrenergic, and opioid targets. The compound was first synthesized in 2019 in the laboratory of David E. Olson at the University of California, Davis, and was identified from a library screen using psychLight, a genetically encoded fluorescent biosensor constructed from the human 5-HT2A receptor with a circularly permuted green fluorescent protein inserted into the third intracellular loop [1]. PsychLight discriminated hallucinogenic from non-hallucinogenic 5-HT2A ligands on the basis of differential conformational activation signatures, and AAZ-A-154 was selected as a lead compound on the basis of its favorable ligand score, a metric that predicted non-hallucinogenic character despite retention of 5-HT2A-dependent psychoplastogenic activity.

    The compound is structurally related to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) but is an isotryptamine (the aminoalkyl side chain is attached to the indole nitrogen at position 1 rather than at position 3), a modification that repositions the compound in chemical space outside classical psychedelic tryptamines. The (R)-enantiomer is the active form; the alpha-methyl substituent on the aminoalkyl chain confers metabolic stability and enantioselective receptor engagement. In rodent models, AAZ-A-154 at doses of 15 to 20 mg/kg intraperitoneally produced rapid-onset (30 minutes) and sustained (7 to 14 days) antidepressant-like behavioral effects in the forced swim test and in the sucrose preference test in VMAT2 heterozygous mice, a genetic model of depressive phenotype [1]. The compound increased dendritic arbor complexity in cultured embryonic rat cortical neurons to a degree comparable to ketamine, and the neuroplastogenic effect was abolished by the 5-HT2 receptor antagonist ketanserin, confirming receptor dependence [1]. Critically, AAZ-A-154 failed to produce the head-twitch response in mice at doses up to 100 mg/kg, the standard behavioral proxy for hallucinogenic activity in the 5-HT2A agonist class [1].

    A comprehensive preclinical characterization published by Agrawal et al. (2025) in ACS Chemical Neuroscience demonstrated that zalsupindole promoted cortical neuritogenesis in vitro, increased dendritic spine density in the prefrontal cortex in vivo, and enhanced measures of functional plasticity to a degree comparable to or greater than ketamine, psilocybin, and N,N-dimethyltryptamine, despite lacking any of the acute cellular and behavioral characteristics of hallucinogenic or dissociative compounds [2]. Pharmacokinetic studies revealed high brain penetrance, rapid distribution, and rapid clearance. In Phase 1 clinical trials enrolling 106 healthy volunteers, oral zalsupindole was well tolerated across a dose range of 2 to 360 mg, with no reports of psychotomimetic, hallucinogenic, or dissociative effects, and with quantitative electroencephalography demonstrating measurable changes in cortical activity consistent with target engagement [3, 4]. A Phase 1b study in 18 adults with major depressive disorder reported clinically meaningful reductions in Montgomery-Asberg Depression Rating Scale scores of approximately 12 points (approximately 50 percent improvement) by Day 8, with effects maintained through Day 36, and comparable efficacy between a seven-day once-daily regimen and a two-dose regimen [5]. No serious adverse events were reported across more than 120 individuals studied. Dose-dependent nausea, headache, and dizziness were the principal mild adverse events. In October 2025, the United States Food and Drug Administration cleared the Investigational New Drug application for a Phase 2, multi-site, randomized, double-blind, placebo-controlled trial in major depressive disorder featuring at-home self-administration [5]. This monograph reviews the chemistry, biosensor-guided discovery, receptor pharmacology, neuroplasticity mechanisms, pharmacokinetics, preclinical and clinical evidence, sourcing and handling, stack interactions, adverse-event signal, and a comparative assessment of five psychoplastogen and rapid-acting antidepressant candidates against AAZ-A-154.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Cogitum

    Acetylated amino acid derivative; synthetic N-acetylaspartate analog with neurometabolic and adaptogenic activity

    A potassium salt of N-acetyl-DL-aminosuccinic acid developed in France as an oral neurometabolic tonic for asthenic syndrome, cognitive fatigue, and pediatric neurodevelopmental delay, distinguished by its structural relationship to endogenous N-acetylaspartate and downstream modulation of glutamatergic and myelinogenic pathways.

    Abstract

    Cogitum is the proprietary pharmaceutical preparation of potassium N-acetyl-DL-aminosuccinate (bipotassium acetylaminosuccinate), a synthetic analog of N-acetylaspartate (NAA), the most concentrated free amino acid derivative in the mammalian central nervous system. The compound was developed in France and patented in the United States in 1969 (US 3,433,875) for the improvement of mental performance in adults experiencing intellectual overwork, memory disorders, and cognitive decline associated with senescence. The active substance provides an exogenous source of the acetylated aspartate moiety that participates in neuronal energy metabolism through the tricarboxylic acid cycle, serves as the obligate precursor for myelin lipid synthesis via oligodendrocytic aspartoacylase-mediated deacetylation, functions as an osmolyte maintaining neuronal volume homeostasis, and is the direct biosynthetic precursor of N-acetylaspartylglutamate (NAAG), the most abundant neuropeptide in the human brain and an endogenous agonist at the presynaptic metabotropic glutamate receptor type 3 (mGluR3). Cogitum is classified pharmacologically as a tonic agent and adaptogen; it is registered and marketed as a drinkable oral solution (250 mg per 10 mL ampoule) in France, Portugal, and several other jurisdictions, and is used extensively in Russian neuropediatric practice for the treatment of asthenic syndrome, attention deficit hyperactivity disorder with subclinical epileptiform activity, speech and language delay, and neurodevelopmental disorders in children aged seven years and older.

    The clinical evidence base includes a 2023 double-blind, randomized, placebo-controlled trial demonstrating that potassium N-acetylaminosuccinate at 750 mg daily for 21 days significantly reduced fatigue scores and improved complex cognitive functions in adults with asthenic syndrome compared to placebo, with no reported adverse events (Esin et al., 2023). Pediatric evidence comprises a 249-patient study in children with ADHD and subclinical epileptiform electroencephalographic activity demonstrating significant improvements in attention, memory, and speech without aggravation of epileptiform discharges or provocation of seizures; additional cohort studies in children with speech delay, traumatic brain injury sequelae, mental retardation, and schizotypal spectrum disorders have reported efficacy in improving cognitive and linguistic performance. The pharmacological rationale rests on the established neurobiology of endogenous N-acetylaspartate: NAA concentrations in the brain reach 10 millimolar or greater, are confined almost exclusively to neurons, and serve as the principal magnetic resonance spectroscopy marker of neuronal viability; reduced NAA is a consistent finding in neurodegenerative disease, traumatic brain injury, multiple sclerosis, and neurodevelopmental disorders. The exogenous provision of the acetylaminosuccinate moiety is hypothesized to support neuronal mitochondrial energy production, to provide acetate substrate for oligodendrocytic myelin lipid synthesis, and to augment NAAG-mediated glutamatergic neuromodulation.

    Safety data across pediatric and adult populations demonstrate excellent tolerability. The compound has no reported cases of overdose toxicity, produces no clinically significant drug interactions at registered doses, and is contraindicated only in cases of known hypersensitivity to the active substance or excipients. The principal limitation of the evidence base is the concentration of clinical research in Russian-language journals with limited replication in Western multicenter trial frameworks. This monograph documents the chemistry, synthesis, mechanism, pharmacokinetics, clinical evidence, sourcing, reconstitution, stack interactions, adverse events, and comparative assessment of Cogitum against five neurometabolic and nootropic alternatives on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Zelquistinel

    Novel positive allosteric modulator of the N-methyl-D-aspartate receptor acting at a unique extracellular binding site independent of the glycine co-agonist site

    A third-generation, orally bioavailable spirocyclic beta-lactam NMDA receptor modulator developed from the rapastinel peptidomimetic platform, distinguished by nanomolar positive allosteric modulation of NR2A-, NR2B-, and NR2C-containing NMDA receptors through reduction of calcium-dependent inactivation, producing rapid and sustained antidepressant-like effects without psychotomimetic liability.

    Abstract

    Zelquistinel (GATE-251, formerly AGN-241751) is a novel, orally bioavailable, small-molecule positive allosteric modulator of the N-methyl-D-aspartate (NMDA) glutamate receptor, currently in Phase 2b clinical development for major depressive disorder (MDD) under the sponsorship of Syndeio Biosciences (operating as Gate Neurosciences). The compound is the third-generation successor to the tetrapeptide rapastinel (GLYX-13) and the dipeptide apimostinel (NRX-1074), sharing a common mechanism of NMDA receptor positive modulation but replacing the peptide scaffold with a spirocyclic 2,5-diazaspiro[3.4]octane (beta-lactam) core that confers oral bioavailability approaching 100 percent in preclinical species, a plasma half-life of approximately 1.2 to 2.1 hours, and approximately 1000-fold greater potency than rapastinel on a weight basis.

    Zelquistinel binds to a unique extracellular site on the NMDA receptor that is distinct from the glutamate agonist site, the glycine co-agonist site, the phencyclidine channel-blocking site, and the polyamine modulatory site. The compound does not displace radioligands at any of these four canonical sites and shows no significant activity across a panel of 80 receptors, ion channels, and monoamine transporters. Mechanistically, zelquistinel acts through a long-distance allosteric pathway: extracellular binding reduces intracellular calcium-dependent inactivation (CDI) of the NMDA receptor channel, thereby enhancing NMDA receptor current in an activity-dependent manner. This mechanism has been demonstrated through experiments showing that replacement of the intracellular calcium chelator EGTA with the fast chelator BAPTA abolishes zelquistinel potentiation, and that removal of the NR1 C-terminal intracellular domain or infusion of calmodulin-blocking peptide similarly eliminates the modulatory effect. Subtype selectivity studies reveal potent enhancement at NR2A-containing (EC50 approximately 9.9 nM) and NR2C-containing (EC50 approximately 9.7 nM) receptors, with a larger ceiling enhancement at NR2B-containing receptors (EC50 approximately 35.0 nM) and no effect at NR2D-containing receptors.

    The pharmacological profile produces a characteristic biphasic, inverted-U dose-response relationship: potentiation of NMDA receptor-mediated calcium influx at concentrations of 0.3 to 60 nM and mild inhibition at concentrations exceeding 100 nM. In preclinical behavioral models, single oral doses of zelquistinel at 30 micrograms per kilogram produce rapid antidepressant-like effects in the forced swim test (onset within one hour) that are sustained for more than seven days, and rescue social approach behavior in the chronic social defeat model at efficacy comparable to ketamine at 10 mg/kg subcutaneous. The compound enhances long-term potentiation (LTP) in both medial prefrontal cortex and hippocampal Schaffer collateral-CA1 pathways, with metaplastic enhancement persisting for at least two weeks after a single dose. Critically, zelquistinel produces no motor impairment on the rotarod test at doses 100-fold above the antidepressant-effective dose and no psychotomimetic symptoms as measured by validated clinical scales in human subjects.

    In Phase 1 clinical evaluation, single ascending oral doses from 100 micrograms to 50 mg were well tolerated in 60 healthy volunteers, with dose-proportional pharmacokinetics, rapid absorption, significant cerebrospinal fluid penetration, and no clinically significant adverse events, vital sign changes, electrocardiographic abnormalities, or psychotomimetic symptoms. A Phase 2a exploratory trial in 251 patients with major depressive disorder demonstrated statistically significant reductions in Montgomery-Asberg Depression Rating Scale (MADRS) scores at the two highest once-weekly oral doses (reductions of 9.5 and 10.6 points versus 7.7 points with placebo at week three). The U.S. Food and Drug Administration granted Fast Track designation for zelquistinel in MDD in July 2018. As of the date of this monograph, a Phase 2b confirmatory trial is actively recruiting under Syndeio Biosciences sponsorship. Additional preclinical research has demonstrated durable relief of core behavioral deficits in three mouse models of autism spectrum disorder, and dose-dependent reversal of phencyclidine-induced hyperlocomotion, expanding the potential therapeutic scope beyond depression.

    This monograph reviews the chemistry, structural class, and synthesis of zelquistinel; the dual extracellular-intracellular allosteric mechanism in molecular and electrophysiological detail; the comprehensive preclinical and human pharmacokinetic record; the clinical evidence base in major depressive disorder; sourcing and quality verification considerations for research applications; reconstitution and handling; stack-interaction implications; adverse-event signal; and a comparative assessment of five NMDA receptor-targeting antidepressant candidates (rapastinel, apimostinel, esketamine, REL-1017, and AV-101) against zelquistinel on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation). The compound is not approved by any regulatory authority for any indication. It is available as a research-grade preparation from chemical suppliers; investigators should obtain analytical confirmation of identity and purity on every lot.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • CT1812

    Selective sigma-2 receptor (TMEM97) complex antagonist with anti-amyloid-beta oligomer synaptoproctective activity

    A first-in-class, orally bioavailable isoindoline sigma-2 receptor antagonist developed by Cognition Therapeutics to displace amyloid-beta oligomers from neuronal synapses, with Phase 2 clinical evidence of cognitive benefit in Alzheimer’s disease and dementia with Lewy bodies.

    Abstract

    CT1812 (zervimesine; CAS 1802632-22-9) is a first-in-class, orally bioavailable small-molecule antagonist of the sigma-2 receptor complex (also designated TMEM97, transmembrane protein 97) developed by Cognition Therapeutics for the treatment of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and geographic atrophy secondary to dry age-related macular degeneration. The compound was identified through a phenotypic neuronal screening assay designed to detect reversal of amyloid-beta oligomer (ABO) induced synaptotoxicity and was chemically optimized from a series of isoindoline scaffolds selected for central nervous system penetration, metabolic stability, and selectivity against cardiac ion channel (hERG) liability. CT1812 binds the sigma-2 receptor with a Ki of 8.5 nM and demonstrates greater than 100-fold selectivity over a broad receptor panel, with approximately 10-fold selectivity over the sigma-1 receptor. The mechanism of action is allosteric antagonism of the sigma-2 receptor complex, which includes TMEM97, progesterone receptor membrane component 1 (PGRMC1), and low-density lipoprotein receptor (LDLR) at the neuronal surface. Engagement of this complex by CT1812 induces a conformational change that displaces prebound amyloid-beta oligomers from synaptic receptors without affecting oligomer assembly or dissociation, thereby restoring synaptic trafficking, reducing synaptotoxicity, and facilitating clearance of oligomers into the cerebrospinal fluid.

    In preclinical studies, CT1812 demonstrated robust brain penetration (brain-to-plasma ratio of 5.7 at 24 hours; unbound brain-to-plasma partition coefficient Kp,uu of 6.75), achieved greater than 84 percent sigma-2 receptor occupancy at therapeutically relevant doses, and improved cognitive performance in transgenic Alzheimer’s mouse models across Y-maze, Morris water maze, and fear conditioning paradigms. The compound is not a P-glycoprotein substrate, exhibits favorable oral absorption with time to peak plasma concentration of 1 to 2 hours and a plasma elimination half-life of approximately 12 hours in humans, and is metabolized primarily by CYP3A4 with secondary contributions from CYP2D6 and CYP2C19.

    A Phase 1 trial in 80 healthy volunteers established safety and tolerability at single doses up to 1120 mg and multiple doses up to 840 mg daily for 14 days, with dose-proportional pharmacokinetics and cerebrospinal fluid penetration achieving estimated receptor occupancy of 97 to 98 percent. A Phase 1b/2 trial (COG0102) in 19 patients with mild to moderate AD demonstrated reductions in cerebrospinal fluid synaptic damage markers (neurogranin and synaptotagmin-1) and decreases of 30 percent or more in six tau phosphorylation sites after 28 days of treatment. The Phase 2 SHINE trial (COG0201) enrolled 153 patients with mild to moderate AD randomized to 100 mg, 300 mg, or placebo for 182 days; the 100 mg dose produced a 39 percent reduction in ADAS-Cog 11 decline relative to placebo, with a 95 percent slowing of cognitive decline in the subpopulation with baseline plasma p-tau217 below the median. The Phase 2 SHIMMER trial (COG1201) enrolled 130 patients with mild to moderate DLB and met its primary safety endpoint; secondary analyses showed 82 percent of treated patients demonstrated slowing on the total Neuropsychiatric Inventory, with a 91 percent reduction in decline of attentional fluctuation measures. CT1812 has also been evaluated in the Phase 2 MAGNIFY trial for geographic atrophy, where treated patients showed 28.6 percent slower lesion growth over 18 months compared to placebo. The compound is generally well tolerated; the principal adverse events are headache, gastrointestinal symptoms (nausea, diarrhea, constipation), and, at the 300 mg dose in SHINE, transient elevations in liver function tests that resolved upon drug discontinuation. CT1812 is positioned for Phase 3 development in Alzheimer’s disease. This monograph reviews the compound identification, discovery and development history, molecular pharmacology, pharmacokinetics, preclinical and clinical evidence, sourcing, reconstitution, stack interactions, safety profile, and a comparative assessment of five alternative approaches to amyloid-beta oligomer or sigma-2 receptor pharmacology.

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  • Cytoflavin

    Fixed-dose combination metabolic cytoprotectant comprising succinic acid, inosine, nicotinamide, and riboflavin for mitochondrial energy rescue and antihypoxant neuroprotection

    A four-component metabolic combination drug developed by POLYSAN Ltd. that supplies Krebs cycle substrate, purine nucleoside, NAD+ precursor, and FAD cofactor to restore aerobic energy production in ischemic, hypoxic, and neurodegenerative tissue.

    Abstract

    Cytoflavin is a fixed-dose combination metabolic agent comprising succinic acid (the principal mass component and Krebs cycle substrate), inosine (a purine nucleoside and precursor to adenine nucleotides), nicotinamide (the amide form of vitamin B3 and precursor to nicotinamide adenine dinucleotide), and riboflavin (vitamin B2, the precursor to flavin adenine dinucleotide and flavin mononucleotide). Developed and manufactured by POLYSAN Scientific and Technological Pharmaceutical Company (Saint Petersburg, Russia), the product is formulated as enteric-coated tablets (300 mg succinic acid, 50 mg inosine, 25 mg nicotinamide, 5 mg riboflavin per tablet) and as a concentrate for intravenous infusion (1000 mg succinic acid, 200 mg inosine, 100 mg nicotinamide, 20 mg riboflavin sodium phosphate per 10 mL ampoule, with meglumine and sodium hydroxide as excipients). The pharmacological rationale is the simultaneous provision of four complementary metabolic substrates and cofactors whose intracellular availability becomes rate-limiting during ischemia, hypoxia, and oxidative stress: succinic acid feeds directly into mitochondrial Complex II (succinate dehydrogenase), bypassing the NAD-dependent steps of the Krebs cycle that fail under hypoxic conditions; inosine supports purine salvage and ATP resynthesis; nicotinamide replenishes the NAD+ pool consumed by poly(ADP-ribose) polymerase activation during ischemic injury; and riboflavin provides the FAD prosthetic group required for succinate dehydrogenase function and for multiple flavoprotein-dependent antioxidant enzymes including glutathione reductase.

    The clinical evidence base for Cytoflavin spans ischemic stroke (acute and chronic cerebral ischemia), traumatic brain injury, diabetic polyneuropathy, postoperative cognitive decline in elderly surgical patients, post-COVID-19 asthenic syndrome, and organic asthenic disorder. The largest and most rigorous published trial is the CYLINDER study, a multicenter, double-blind, placebo-controlled, randomized trial in 216 patients with type 2 diabetes mellitus and symptomatic distal sensorimotor diabetic polyneuropathy conducted across 10 Russian clinical centers, which reported a statistically significant reduction in Total Symptom Score (TSS change of negative 2.65 points in the experimental group versus negative 1.73 points in the placebo group, p less than 0.001) after a sequential intravenous-then-oral treatment regimen. In acute ischemic stroke, multicenter studies have demonstrated marked reduction in neurological deficit severity by day 10 and higher probability of favorable functional outcome compared to standard-of-care controls. The CITADEL prospective randomized study demonstrated a pronounced anti-asthenic effect and correction of cognitive impairments in post-COVID-19 rehabilitation. An international, multicenter, randomized, single-blind, placebo-controlled trial (NCT04631484) evaluating Cytoflavin in moderate traumatic brain injury in adults was completed in 2024, with results published in Frontiers in Neurology in 2025, representing the first large-scale international trial of the compound outside the Russian Federation and Commonwealth of Independent States.

    Cytoflavin is registered as a medicinal product in the Russian Federation and in Vietnam. The manufacturing facility holds GMP EU certification. The compound is not approved by the United States Food and Drug Administration, by the European Medicines Agency, or by other major Western regulatory authorities. The clinical literature is predominantly in Russian-language journals, with an expanding body of English-language publications in international peer-reviewed venues. The safety profile across published clinical studies is favorable; the principal adverse events are transient epigastric discomfort, headache, hyperuricemia (attributable to inosine-derived purine catabolism), and rare hypersensitivity reactions. No serious adverse events attributable to the drug have been reported in published controlled trials.

    This monograph reviews the composition, identification, and formulation chemistry of Cytoflavin; the individual and composite pharmacology of its four active components; the pharmacokinetic considerations for each component; the preclinical pharmacology; the clinical evidence base across all studied indications; sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signals; and a comparative assessment of five alternative neuroprotective metabolic agents (Mexidol, Actovegin, Cerebrolysin, citicoline, and Reamberin) against Cytoflavin on five competency standards.

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  • Alpha-Klotho

    Type I transmembrane protein and circulating endocrine factor of the glycosyl hydrolase family 1 superfamily with obligate FGF23 co-receptor and pleiotropic anti-aging functions

    A kidney-derived transmembrane glycoprotein and its shed soluble ectodomain, identified through insertional mutagenesis in 1997 as a suppressor of aging phenotypes in mice, functioning both as an obligate co-receptor for fibroblast growth factor 23 in mineral metabolism and as a circulating endocrine factor that inhibits insulin/IGF-1, Wnt, TGF-beta, and NF-kappaB signaling pathways with demonstrated neuroprotective, cardioprotective, and renoprotective activity in preclinical models.

    Abstract

    Alpha-Klotho (alpha-KL) is a 130 kDa type I single-pass transmembrane protein encoded by the KL gene on human chromosome 13q13.1, first identified in 1997 by Kuro-o et al. through characterization of an insertional mutation in mice that produced a syndrome of accelerated aging encompassing soft tissue calcification, arteriosclerosis, skin atrophy, osteoporosis, emphysema, gonadal dysplasia, and dramatically shortened lifespan [1]. The protein comprises a short intracellular domain, a single transmembrane helix, and a large extracellular region containing two tandem glycosyl hydrolase family 1 (GH1) domains, designated KL1 and KL2, which share sequence homology with family 1 beta-glucosidases but lack catalytic activity against conventional substrates due to substitutions in the active-site residues. The extracellular domain undergoes proteolytic shedding by ADAM10, ADAM17, and BACE1, generating a soluble ectodomain (sKL) comprising KL1 and KL2 that circulates as an endocrine factor detectable in plasma, cerebrospinal fluid, and urine. A shorter secreted isoform containing only KL1 is produced by alternative mRNA splicing.

    In its membrane-bound form, alpha-Klotho functions as an obligate co-receptor for fibroblast growth factor 23 (FGF23), forming a ternary complex with FGF receptor 1c (FGFR1c) that is essential for phosphaturic signaling in the renal proximal tubule and for suppression of 1,25-dihydroxyvitamin D3 (calcitriol) synthesis. The crystal structure of the alpha-Klotho/FGFR1c/FGF23 ternary complex, resolved by Chen et al. (2018) at 3.0 angstrom resolution, demonstrated that the KL2 domain of alpha-Klotho cradles FGF23 with a receptor-binding arm extending from the KL1-KL2 interdomain cleft, creating a composite binding surface for FGF23 engagement [2]. Loss of this co-receptor function produces the hyperphosphatemia, hypervitaminosis D, and ectopic calcification that characterize the kl/kl mouse phenotype and that are recapitulated in FGF23 knockout mice.

    Independent of the FGF23 co-receptor function, soluble alpha-Klotho acts as a circulating endocrine factor with pleiotropic anti-aging activity. Characterized signaling activities include inhibition of the insulin/insulin-like growth factor 1 (IGF-1) pathway through suppression of receptor autophosphorylation; suppression of Wnt/beta-catenin signaling through direct binding to Wnt ligands; inhibition of transforming growth factor beta (TGF-beta) type II receptor signaling and downstream Smad phosphorylation; suppression of NF-kappaB-driven inflammatory transcription; and regulation of ion channel and transporter activity in the renal tubule, including TRPV5, TRPV6, ROMK1, and the Na+/K+-ATPase [3, 4, 5]. These FGF23-independent activities are the molecular basis for the broader anti-aging, neuroprotective, cardioprotective, and anti-fibrotic effects observed in gain-of-function and supplementation studies.

    Circulating soluble alpha-Klotho levels decline with age in humans, beginning approximately in the fourth decade of life, and are markedly reduced in chronic kidney disease, where loss of renal alpha-Klotho expression precedes and contributes to the mineral and bone disorder, cardiovascular calcification, and accelerated aging phenotype of uremia [6]. Epidemiological studies have identified inverse associations between circulating soluble alpha-Klotho concentrations and all-cause mortality, cardiovascular events, and cognitive decline in community-dwelling older adults [7]. The KL-VS haplotype (defined by the F352V and C370S variants, rs9536314 and rs9527025) has been associated in some cohorts with altered klotho secretion, cortical brain volume, and cognitive resilience in aging, though replication across large cohorts remains inconsistent [8, 9].

    Preclinical studies have demonstrated that recombinant alpha-Klotho protein administration, adeno-associated virus-mediated KL gene transfer, and transgenic KL overexpression produce renoprotection in ischemia-reperfusion injury and unilateral ureteral obstruction models; cardioprotection with attenuation of left ventricular hypertrophy and fibrosis; suppression of vascular calcification; and cognitive enhancement in aged, young, and alpha-synuclein transgenic mice through NMDA receptor-dependent glutamatergic mechanisms [10, 11, 12, 13]. A 2023 study in aged nonhuman primates demonstrated that a single subcutaneous injection of a klotho protein fragment enhanced spatial and working memory, representing the first primate cognitive enhancement data for the compound [14].

    As of 2026, alpha-Klotho is in early clinical development. Klothea Bio launched a Phase 1b randomized, double-blind, placebo-controlled trial of AKL003, an alpha-Klotho mRNA therapeutic administered intravenously, in healthy adult volunteers in February 2026. Klotho Neurosciences is advancing KLTO-202, a KL gene therapy, toward first-in-human studies for amyotrophic lateral sclerosis. No alpha-Klotho protein or gene therapy product has received regulatory approval in any jurisdiction. Recombinant human alpha-Klotho protein is available from multiple research suppliers (R&D Systems, Abcam, Sino Biological, Thermo Fisher) for in vitro and preclinical applications. This monograph reviews the molecular identification, structural biology, receptor pharmacology, preclinical pharmacology across organ systems, the emerging clinical evidence base, sourcing and handling considerations, stack interactions, safety signal, and a comparative assessment of five anti-aging intervention candidates against alpha-Klotho on five competency standards.

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  • Apelin-13

    Endogenous bioactive peptide agonist of the apelin receptor (APJ/APLNR), a class A G protein-coupled receptor

    A pyroglutamyl-modified tridecapeptide derived from the C-terminus of preproapelin, identified as the predominant circulating isoform and the highest-potency endogenous agonist of the APJ receptor, with characterized cardiovascular inotropic, vasodilatory, aquaretic, metabolic, and neuroprotective activities.

    Abstract

    Apelin-13, the C-terminal tridecapeptide fragment of the 77-amino-acid preproapelin precursor, is the most potent endogenous agonist of the apelin receptor (APJ, also designated APLNR), a class A rhodopsin-like G protein-coupled receptor originally cloned as an orphan receptor in 1993 by O’Dowd et al. on the basis of sequence homology with the angiotensin II type 1 receptor. The receptor was deorphanized in 1998 by Tatemoto and colleagues at the Takeda Chemical Research Institute, who isolated apelin from bovine stomach extracts using an extracellular acidification assay on APJ-expressing Chinese hamster ovary cells and demonstrated that apelin-13 displayed 8- to 60-fold higher potency than the longer apelin-36 isoform. The predominant circulating form in human plasma is [Pyr1]apelin-13 (pyroglutamyl apelin-13), in which the N-terminal glutamine residue undergoes spontaneous or enzymatic cyclization to pyroglutamate, conferring modest resistance to aminopeptidase degradation and representing the principal bioactive isoform in cardiovascular tissue and plasma.

    Apelin-13 activates APJ with sub-nanomolar potency (EC50 approximately 0.37 nM in cellular acidification assays), coupling predominantly through Gi/o proteins to inhibit adenylyl cyclase and reduce intracellular cAMP, through Gq/11 to activate phospholipase C and mobilize intracellular calcium, and through G12/13 to engage RhoA-dependent cytoskeletal rearrangement. The receptor also recruits beta-arrestin 1 and 2, mediating receptor internalization and activating extracellular signal-regulated kinase 1/2 (ERK1/2) through G protein-independent pathways. The downstream signaling cascade includes activation of phosphoinositide 3-kinase (PI3K)/Akt, endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and inhibition of reactive oxygen species generation, collectively producing the cardiovascular, metabolic, and cytoprotective effects that define the pharmacological profile.

    The cardiovascular pharmacology of apelin-13 is the most extensively characterized domain. In human clinical studies, systemic infusion of [Pyr1]apelin-13 at 30 to 300 nmol/min produces a sustained approximately 10 percent increase in cardiac index, increased ejection fraction, reduced systemic vascular resistance by approximately 12 percent, and reduced mean arterial pressure by approximately 4 percent, effects observed in both healthy volunteers and patients with chronic heart failure and chronic kidney disease. The mechanism involves direct positive inotropic action on cardiomyocytes through APJ-mediated calcium sensitization, nitric oxide-dependent vasodilation in resistance arteries, and counter-regulatory opposition to the renin-angiotensin-aldosterone system. Preclinical models demonstrate cardioprotective effects in myocardial infarction, ischemia-reperfusion injury, pressure-overload hypertrophy, and diabetic cardiomyopathy, with mechanisms including salvage of the peri-infarct border zone, mobilization of endogenous cardiac stem cells, and suppression of pathological fibrosis.

    The renal pharmacology is defined by the functional antagonism between apelin and arginine vasopressin (AVP) at the collecting duct. Apelin-13 inhibits vasopressin-induced translocation of aquaporin 2 (AQP2) water channels to the apical membrane of principal cells through Gi-mediated inhibition of cAMP/protein kinase A signaling, producing a diuretic (aquaretic) effect that opposes AVP-driven water reabsorption. This reciprocal regulation positions the apelin/AVP axis as a physiological rheostat for water homeostasis, with therapeutic implications for hyponatremia and states of AVP excess.

    Metabolic pharmacology encompasses insulin-sensitizing and glucoregulatory effects. Apelin-13 administration in diabetic rodent models reduces blood glucose, increases serum insulin, improves pancreatic islet mass, and enhances glucose uptake in skeletal muscle through AMPK-dependent GLUT4 translocation. Neuroprotective activity has been demonstrated in models of ischemic stroke, diabetes-associated cognitive decline, and excitotoxic injury, with mechanisms including antioxidant defense through the SIRT3/FoxO3 pathway, anti-inflammatory cytokine modulation, and direct neuronal survival signaling through PI3K/Akt.

    The principal pharmacokinetic limitation of apelin-13 is its extremely short plasma half-life. Native [Pyr1]apelin-13 has a plasma half-life of approximately 21 to 24 minutes in rodents, driven by rapid proteolytic degradation at the Leu5-Ser6 peptide bond by neprilysin, angiotensin-converting enzyme 2 (ACE2), and plasma kallikrein. This has motivated extensive medicinal chemistry efforts to develop stabilized analogues (macrocyclic peptides, D-amino acid substitutions, PEGylation) and small-molecule APJ agonists (AMG-986, BMS-986224, azelaprag) for chronic administration.

    This monograph reviews the chemistry, identification, and structural biology of apelin-13; the discovery and deorphanization history of the APJ receptor; the molecular pharmacology across Gi, Gq, G12/13, and beta-arrestin pathways; the pharmacokinetic profile and proteolytic degradation pathways; the preclinical evidence base across cardiovascular, renal, metabolic, and neurological domains; the clinical evidence from human hemodynamic studies; sourcing and quality verification for research-grade material; reconstitution and handling protocols; stack interactions with vasoactive and metabolic agents; the adverse-event and safety profile; and a comparative assessment of five APJ receptor agonist candidates against apelin-13 on five competency standards. The compound is not an approved therapeutic agent in any jurisdiction. It is supplied as a research-grade peptide; investigators should obtain analytical confirmation of identity, purity, and peptide content on every lot.

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