Category: Uncategorized

  • Bryostatin-1

    Macrocyclic lactone protein kinase C modulator with sub-nanomolar affinity for the C1 regulatory domain

    A marine-derived macrolide isolated from the bryozoan Bugula neritina, distinguished from classical phorbol ester PKC activators by isoform-selective modulation producing anti-inflammatory, synaptogenic, and latent HIV-reversing activity at sub-nanomolar concentrations without tumor-promoting effects.

    Abstract

    Bryostatin-1, the prototypical member of the bryostatin family of macrocyclic lactones, is a highly oxygenated 26-membered macrolide originally isolated from the marine bryozoan Bugula neritina and subsequently attributed to the bacterial endosymbiont Candidatus Endobugula sertula. The compound binds the C1 regulatory domain of protein kinase C (PKC) at the conserved diacylglycerol (DAG) binding site with sub-nanomolar affinity, modulating both conventional (alpha, betaI/betaII, gamma) and novel (delta, epsilon, eta, theta) PKC isoforms. Despite competitive displacement of phorbol esters from the C1 domain, bryostatin-1 produces functionally distinct downstream signaling characterized by initial PKC activation followed by isoform-selective downregulation, a pharmacological profile that distinguishes it from tumor-promoting phorbol esters and underwrites its diverse therapeutic applications across oncology, neurology, immunology, and infectious disease.

    The compound entered clinical development through the National Cancer Institute (NCI) in the early 1990s as an antineoplastic agent, advancing through more than 80 Phase 1 and Phase 2 oncology trials enrolling over 1,500 patients across multiple solid tumor and hematological malignancy indications. The principal dose-limiting toxicity in oncology trials was myalgia, observed at doses of 25 to 50 micrograms per square meter administered by intravenous infusion. Single-agent antitumor activity was modest, though combination regimens with cytarabine in acute myeloid leukemia and with vincristine in non-Hodgkin lymphoma produced response rates warranting further investigation. The oncology program did not yield a registration-quality efficacy signal, and active NCI-sponsored oncology development was substantially curtailed by 2010.

    A second clinical trajectory, initiated by Alkon and colleagues at the Blanchette Rockefeller Neurosciences Institute and subsequently advanced by Synaptogenix (formerly Neurotrope), repositioned bryostatin-1 as a cognitive enhancement agent for Alzheimer’s disease on the basis of PKC epsilon activation, synaptogenesis induction, and amyloid precursor protein alpha-secretase processing. A Phase 2a trial (Nelson et al. 2017) demonstrated safety at 25 micrograms per square meter and produced signals of PKC epsilon activation and cognitive stabilization. A larger NIH-sponsored Phase 2 trial (NCT04538066) in 122 patients with moderately severe Alzheimer’s disease reported that the primary endpoint (change from baseline in Severe Impairment Battery score at week 28) was not met with statistical significance across the full analysis population. However, prespecified secondary analysis of the severe cohort (Mini-Mental State Examination 10 to 14) demonstrated that bryostatin-treated patients showed no significant cognitive decline over 10 months, compared with placebo patients who declined by 12.8 Severe Impairment Battery points, a finding published in the Journal of Alzheimer’s Disease in 2023. The compound was well tolerated in the Alzheimer’s trials with no drug-related serious adverse events and no cases of the myalgia observed at higher oncology doses.

    A third research application addresses HIV latency reversal. Bryostatin-1 reactivates latent HIV-1 provirus through PKC-mediated NF-kappaB activation in both lymphocytic and monocytic cellular reservoirs, including astrocytes, at low nanomolar concentrations. The Wender laboratory at Stanford developed a scalable 29-step total synthesis (2017) and characterized synthetic bryostatin analogs (bryologs) as latency-reversing agents with an expanded therapeutic window, establishing the foundation for a “kick and kill” eradication strategy in combination with antiretroviral therapy.

    Pharmacokinetics following intravenous administration are characterized by a two-compartment disposition model with distribution and elimination half-lives of approximately 1 and 23 hours, respectively. The compound distributes widely to lung, liver, gastrointestinal tract, and adipose tissue, with evidence of enterohepatic circulation. Renal excretion accounts for approximately 23 percent of the administered dose in the first 12 hours; fecal excretion accounts for approximately 40 percent by 72 hours. The compound is not orally bioavailable at therapeutically relevant concentrations and is administered exclusively by intravenous infusion in clinical applications.

    This monograph reviews the chemistry, natural source, total synthesis, and supply chain of bryostatin-1; the PKC isoform pharmacology in molecular detail; the comprehensive pharmacokinetic record; the clinical evidence base across oncology, Alzheimer’s disease, and HIV latency reversal indications; reconstitution, sourcing, and handling considerations for laboratory work; stack-interaction implications; the adverse-event and safety profile; and a comparative assessment of five PKC-modulating compounds (prostratin, ingenol mebutate, phorbol 12-myristate 13-acetate, SUW133, and TPPB) against bryostatin-1 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 supplied as a research-grade preparation; investigators should obtain analytical confirmation of identity and purity on every lot.

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  • 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.

  • GlyNAC

    Glutathione precursor amino acid combination providing glycine and N-acetylcysteine as rate-limiting substrates for intracellular glutathione biosynthesis

    A defined combination of glycine and N-acetylcysteine developed at Baylor College of Medicine as a glutathione-replenishing intervention targeting age-associated oxidative stress, mitochondrial dysfunction, and multiple hallmarks of biological aging.

    Abstract

    GlyNAC is a defined equimolar combination of glycine and N-acetylcysteine (NAC) that supplies the two amino acid precursors whose availability limits the intracellular biosynthesis of glutathione (gamma-glutamylcysteinylglycine, GSH), the most abundant endogenous non-protein thiol antioxidant in mammalian cells. The combination was developed and systematically investigated by Rajagopal V. Sekhar and colleagues at Baylor College of Medicine beginning approximately 2018, on the basis of prior observations that aging, HIV infection, and type 2 diabetes are associated with deficient intracellular glutathione concentrations traceable to diminished availability of both glycine and cysteine rather than to reduced activity of the synthetic enzymes glutamate-cysteine ligase and glutathione synthetase. The mechanistic rationale is that NAC undergoes deacetylation to cysteine in the intestinal mucosa and liver, while supplemental glycine directly enters the glutathione synthetic pathway; co-administration of both precursors at physiologically relevant doses corrects the dual substrate deficit and restores intracellular glutathione concentrations within two weeks in human subjects, with downstream improvements in oxidative stress biomarkers, mitochondrial fatty-acid oxidation, inflammation, insulin resistance, endothelial function, genomic integrity, and cellular senescence markers.

    The principal clinical evidence derives from a series of trials conducted at Baylor College of Medicine. A 36-week open-label pilot trial in older adults (aged 61 to 80 years) demonstrated that 24 weeks of GlyNAC supplementation at approximately 100 milligrams per kilogram per day of each component (approximately 7 grams of glycine and 7 grams of NAC daily for a 70-kilogram adult) corrected red blood cell glutathione deficiency, reduced plasma markers of oxidative stress (thiobarbituric acid reactive substances, F2-isoprostanes), improved mitochondrial fatty-acid oxidation by indirect calorimetry, lowered fasting insulin resistance (homeostatic model assessment of insulin resistance), improved grip strength and gait speed, and improved cognitive scores on the Montreal Cognitive Assessment; benefits receded within 12 weeks of supplementation withdrawal. A subsequent double-blind, placebo-controlled randomized clinical trial in 24 older adults (aged 65 to 80 years) confirmed these findings over 16 weeks of supplementation, with additional demonstration of improvements in multiple hallmarks of aging including mitochondrial dysfunction, impaired mitophagy, inflammation, endothelial dysfunction, genomic damage, stem cell fatigue, and cellular senescence. An independent dose-finding randomized controlled trial conducted by the Nestle Institute of Health Sciences in 114 healthy older adults tested three dose tiers (2.4, 4.8, and 7.2 grams per day total in a 1:1 glycine-to-NAC ratio) over two weeks and confirmed dose-dependent increases in plasma glycine and cysteine concentrations and in erythrocyte glutathione.

    Parallel investigations have extended the GlyNAC evidence base to HIV-infected adults (open-label, improvements in oxidative stress, mitochondrial function, inflammation, endothelial function, insulin resistance, strength, and cognition), type 2 diabetes (pilot study, 30 percent improvement in mitochondrial fatty-acid oxidation and 22 percent reduction in insulin resistance over 14 days), and COVID-19 (observational characterization of severe glutathione deficiency and oxidative stress in hospitalized patients). A preclinical mouse lifespan study demonstrated that GlyNAC supplementation initiated at 65 weeks of age (corresponding to late middle age in humans) extended median lifespan by 24 percent and corrected glutathione deficiency, oxidative stress, mitochondrial dysfunction, impaired mitophagy, abnormal nutrient sensing, and genomic damage in liver, heart, and kidney tissues.

    The combination is well tolerated in all published trials. No serious adverse events attributable to GlyNAC have been reported. The principal mild adverse events are gastrointestinal (nausea, bloating), attributable to the NAC component, and are dose-dependent and generally self-limiting. The glycine component has an extensive safety record as a dietary amino acid and as a research compound at doses up to 60 grams per day in schizophrenia trials. NAC has an established clinical safety profile as a mucolytic and acetaminophen-overdose antidote at doses substantially exceeding those used in GlyNAC research.

    This monograph documents the composition, molecular pharmacology, and glutathione biosynthetic rationale of GlyNAC; the pharmacokinetics of the individual components; the complete preclinical and clinical evidence base across aging, HIV, diabetes, and COVID-19 indications; sourcing and quality verification; reconstitution and handling; stack interactions; the adverse-event profile; and a comparative assessment of five alternative glutathione-replenishing strategies (N-acetylcysteine alone, oral reduced glutathione, liposomal glutathione, alpha-lipoic acid, and whey protein concentrate) against GlyNAC on five competency standards (mechanistic completeness, effect size, clinical validation, side-effect profile, and practical accessibility).

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  • Verteporfin

    Benzoporphyrin derivative photosensitizer with light-independent YAP-TEAD transcriptional complex inhibition

    A second-generation benzoporphyrin derivative photosensitizer approved for ocular photodynamic therapy, distinguished from first-generation porphyrins by rapid clearance, selective vascular targeting, and a pharmacologically independent capacity to disrupt the YAP-TEAD transcriptional complex implicated in Hippo pathway dysregulation and solid tumor progression.

    Abstract

    Verteporfin (benzoporphyrin derivative monoacid ring A, BPD-MA, CL 318952) is a semi-synthetic chlorin-class photosensitizer derived from protoporphyrin IX and approved by the United States Food and Drug Administration since April 2000 for the photodynamic therapy of predominantly classic subfoveal choroidal neovascularization secondary to age-related macular degeneration, pathologic myopia, and presumed ocular histoplasmosis syndrome. Marketed as Visudyne by QLT PhotoTherapeutics (subsequently Bausch and Lomb), the compound represented the first pharmacological intervention for neovascular age-related macular degeneration and established ocular photodynamic therapy as a standard of care prior to the introduction of anti-vascular endothelial growth factor agents. The photodynamic mechanism operates through selective accumulation in neovascular endothelium via lipoprotein-mediated uptake, followed by activation with 689 nm non-thermal laser light to generate reactive oxygen species (singlet oxygen and superoxide) that produce localized vascular endothelial damage, thrombosis, and vessel occlusion without thermal injury to the overlying neurosensory retina.

    Independent of its photosensitizing activity, verteporfin was identified in 2012 by Liu-Chittenden et al. as a small-molecule inhibitor of the Yes-associated protein (YAP) and transcriptional enhanced associate domain (TEAD) protein-protein interaction, a critical effector node of the Hippo tumor suppressor pathway [1]. This discovery initiated a substantial and expanding preclinical oncology literature demonstrating that verteporfin, without photoactivation, suppresses YAP-driven transcription, inhibits proliferation and invasion, and produces survival benefit in xenograft and orthotopic models of glioblastoma, pancreatic ductal adenocarcinoma, ovarian carcinoma, hepatocellular carcinoma, colorectal carcinoma, melanoma, and retinoblastoma [2, 3, 4, 5]. The YAP-TEAD inhibitory mechanism involves direct binding to YAP that alters its conformation and prevents association with TEAD transcription factors, upregulation of 14-3-3 sigma (stratifin) that sequesters YAP in the cytoplasm, and suppression of downstream targets including connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61) [6, 7].

    Pharmacokinetics following the approved intravenous dose of 6 mg per square meter of body surface area are characterized by biexponential disposition with a distribution phase of 1 to 3 hours and a terminal elimination half-life of 5 to 6 hours. Verteporfin is 90 percent associated with plasma lipoproteins (principally low-density lipoprotein) and approximately 6 percent with albumin. Metabolism is limited and occurs through liver and plasma esterases to the diacid metabolite BPD-DA; cytochrome P450 enzymes do not contribute meaningfully to elimination. Excretion is predominantly fecal as unchanged drug, with less than 0.01 percent recovered in urine [8, 9].

    This monograph reviews the chemistry, synthesis, and photophysics of verteporfin; the dual mechanism encompassing photodynamic vascular occlusion and light-independent YAP-TEAD inhibition; the comprehensive pharmacokinetic record; the clinical evidence base across ophthalmic and investigational oncologic indications; sourcing and quality verification for research applications; reconstitution and handling protocols; stack-interaction considerations; adverse-event signal including photosensitivity; and a comparative assessment of five alternative photosensitizers or YAP pathway inhibitors against verteporfin 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.

  • AMX0035

    Fixed-dose oral combination of sodium phenylbutyrate (chemical chaperone and HDAC inhibitor) and taurursodiol (bile acid cytoprotectant) targeting endoplasmic reticulum stress and mitochondrial dysfunction

    A proprietary two-component oral formulation developed by Amylyx Pharmaceuticals combining sodium phenylbutyrate and taurursodiol (tauroursodeoxycholic acid) to concurrently attenuate endoplasmic reticulum stress and mitochondrial apoptotic signaling in neurodegenerative disease, approved under accelerated pathway by the United States Food and Drug Administration in September 2022 for the treatment of amyotrophic lateral sclerosis in adults and subsequently withdrawn from the market in 2024 following failure to confirm efficacy in the confirmatory Phase 3 PHOENIX trial.

    Abstract

    AMX0035, marketed as Relyvrio in the United States and Albrioza in Canada, is a fixed-dose oral combination of sodium phenylbutyrate (3 grams per sachet) and taurursodiol (1 gram per sachet) developed by Amylyx Pharmaceuticals for the treatment of amyotrophic lateral sclerosis (ALS) and under investigation for Alzheimer disease. The therapeutic rationale is simultaneous modulation of two convergent cell-death pathways implicated in motor neuron degeneration: endoplasmic reticulum (ER) stress, addressed by the chemical chaperone and histone deacetylase (HDAC) inhibitor activity of sodium phenylbutyrate, and mitochondrial apoptotic signaling, addressed by the bile acid cytoprotectant taurursodiol (the taurine conjugate of ursodeoxycholic acid). Sodium phenylbutyrate upregulates molecular chaperones including heat shock protein 70 (HSP70) and DJ-1, reduces accumulation of misfolded proteins in the ER lumen, and inhibits class I and class II histone deacetylases (excluding class III, HDAC6, and HDAC10), thereby promoting a transcriptional program favoring cell survival. Taurursodiol stabilizes the mitochondrial membrane by inhibiting Bax translocation, reducing mitochondrial permeability transition pore opening, and raising the apoptotic threshold by preventing cytochrome c release into the cytosol. In preclinical models, the combination produced synergistic reduction of hydrogen peroxide-induced neuronal cell death beyond either component alone.

    The clinical evidence base for AMX0035 in ALS rests principally on the Phase 2 CENTAUR trial (NCT03127514), a 24-week, randomized, double-blind, placebo-controlled study conducted across 25 Northeast ALS Consortium (NEALS) sites in 137 participants with ALS of no more than 18 months symptom duration [1]. The primary endpoint was the rate of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R): participants receiving AMX0035 showed a mean decline of 1.24 points per month versus 1.66 points per month on placebo, a difference of 0.42 points per month (95% CI 0.03 to 0.81; p = 0.03). Long-term survival analysis of the CENTAUR cohort showed a median survival advantage of 6.5 months favoring those originally randomized to AMX0035 (hazard ratio 0.57; 95% CI 0.35 to 0.92; p = 0.023) [2]. On the basis of these Phase 2 data and an external-control survival analysis, the FDA granted accelerated approval to Relyvrio on September 29, 2022, for the treatment of ALS in adults. Health Canada had previously granted approval to Albrioza in June 2022.

    The confirmatory Phase 3 PHOENIX trial (NCT05021536), a 48-week, randomized, placebo-controlled study in 664 adults with ALS, did not meet its primary endpoint of slowing ALSFRS-R decline (p = 0.667) or any secondary endpoints [3]. No significant treatment effect was observed even in the subset of participants who met the original CENTAUR eligibility criteria. Following the PHOENIX results, Amylyx Pharmaceuticals discontinued marketing of Relyvrio as of October 31, 2024, and submitted a formal request for withdrawal of FDA approval on February 28, 2025. The European Medicines Agency had previously declined to authorize the compound for marketing in the European Union.

    A separate Phase 2 trial (PEGASUS) evaluated AMX0035 in 96 adults with mild cognitive impairment or dementia due to Alzheimer disease over 24 weeks [4]. The trial met its primary endpoint of safety and tolerability but did not demonstrate slowing of cognitive decline. AMX0035 produced significant reductions in cerebrospinal fluid biomarkers of tau pathology (phosphorylated tau 181 and total tau, both p < 0.001) and modulation of the amyloid beta 42/40 ratio (p < 0.05), suggesting biological activity on core Alzheimer disease pathology despite the absence of a clinical cognitive signal in this short-duration study.

    The pharmacokinetics of the two components are well characterized independently. Sodium phenylbutyrate is rapidly absorbed (Tmax approximately 1 hour), with a plasma half-life of approximately 0.76 hours, and is metabolized by beta-oxidation to phenylacetate (half-life approximately 1.2 hours) and subsequently conjugated with glutamine to form phenylacetylglutamine, which is renally excreted. Taurursodiol, a hydrophilic bile acid conjugate, undergoes hepatic first-pass extraction via bile acid transporters, enters the enterohepatic circulation, and is metabolized by intestinal bacteria; systemic bioavailability is limited by efficient hepatic uptake. The combination is administered as a powder for oral suspension, mixed in 250 milliliters of water, taken once daily for the first three weeks and twice daily thereafter. The principal adverse events are gastrointestinal (diarrhea, abdominal pain, nausea), occurring predominantly during the first three weeks of dosing, with rates of discontinuation due to adverse events of approximately 19 percent in the CENTAUR trial compared to 8 percent on placebo.

    This monograph reviews the chemistry, formulation, and component pharmacology of AMX0035; the dual-pathway mechanistic rationale; the complete pharmacokinetic profiles of both components; the preclinical neuroprotection data; the clinical evidence from CENTAUR, PHOENIX, and PEGASUS; sourcing, reconstitution, and handling considerations; stack interactions; the adverse-event and safety profile; and a comparative assessment of five alternative ALS therapeutic agents (riluzole, edaravone, tofersen, masitinib, and dexpramipexole) against AMX0035 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.

  • 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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  • Astragaloside IV

    Cycloartane-type triterpenoid saponin glycoside derived from Astragalus membranaceus with pleiotropic anti-inflammatory, antioxidant, and cytoprotective activity

    A cycloartane triterpenoid saponin isolated from Astragalus membranaceus (Huangqi) that modulates NF-kB, PI3K/Akt, and Nrf2/HO-1 signaling to produce cardioprotective, neuroprotective, hepatoprotective, and immunomodulatory effects across a broad preclinical evidence base.

    Abstract

    Astragaloside IV (AS-IV) is a cycloartane-type triterpenoid saponin glycoside and the principal pharmacologically active saponin constituent of Astragalus membranaceus (Huangqi), a botanical drug with over two thousand years of documented use in traditional Chinese medicine for tonification of qi, immune support, and cardiovascular health. The compound, bearing the molecular formula C41H68O14 and a molecular weight of 784.97, consists of a cycloartane aglycone skeleton conjugated to beta-D-glucose and beta-D-xylose sugar moieties. Astragaloside IV has emerged over the past two decades as one of the most extensively investigated natural product saponins in modern pharmacology, with a research literature now spanning cardioprotection, neuroprotection, hepatoprotection, nephroprotection, pulmonary fibrosis attenuation, anti-tumor activity, metabolic syndrome modulation, and telomerase activation through its principal gut-microbial metabolite cycloastragenol.

    The molecular pharmacology of astragaloside IV is characterized by multi-target activity across several canonical signaling cascades. The compound inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway through suppression of IkB phosphorylation and reduction of nuclear translocation, producing dose-dependent reductions in tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 in activated macrophages and in lipopolysaccharide-challenged animal models. Concurrently, astragaloside IV activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant response element pathway, upregulating superoxide dismutase, glutathione peroxidase, and catalase expression. The compound modulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling axis with context-dependent activation (cardioprotection, neuroprotection) or inhibition (anti-tumor applications), and suppresses the transforming growth factor beta 1 (TGF-beta1)/Smad pathway to attenuate fibrotic remodeling in lung, liver, and kidney tissue. Additional characterized targets include Toll-like receptor 4 (TLR4), the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPARgamma), and glycogen synthase kinase 3 beta (GSK3beta).

    Pharmacokinetics present the principal translational challenge for astragaloside IV. Oral bioavailability in rats is approximately 2.2 to 3.7 percent, and in beagle dogs approximately 7.4 percent, reflecting high molecular weight, poor aqueous solubility, limited intestinal membrane permeability, and predominantly paracellular absorption. The compound undergoes extensive biotransformation by intestinal microflora (principally Bifidobacteria and Lactobacillus species) through sequential deglycosylation to produce cycloastragenol, the aglycone metabolite that is substantially more bioavailable and that mediates telomerase activation through upregulation of human telomerase reverse transcriptase (hTERT) gene expression via the mitogen-activated protein kinase (MAPK) pathway. Plasma elimination half-life in rats after oral administration is approximately 3.8 hours, with highest tissue concentrations in lung and liver.

    The preclinical evidence base is extensive and spans multiple organ systems. In myocardial ischemia-reperfusion models, astragaloside IV at doses of 10 to 80 mg/kg reduces infarct size, improves ejection fraction, and attenuates apoptosis through PI3K/Akt and mitochondrial pathway modulation. In focal cerebral ischemia models, the compound reduces infarct volume and neurological deficit scores through Nrf2/HO-1 activation and NF-kB suppression. In carbon tetrachloride and high-fat-diet hepatotoxicity models, astragaloside IV preserves hepatocyte integrity through antioxidant and anti-inflammatory mechanisms. In diabetic nephropathy models, the compound attenuates glomerular basement membrane thickening and reduces proteinuria. In bleomycin-induced pulmonary fibrosis models, astragaloside IV suppresses collagen deposition through TGF-beta1/Smad pathway inhibition.

    Clinical evidence in humans remains limited. Safety data from Phase 1 studies of an intravenous astragaloside IV preparation in healthy Chinese volunteers demonstrated tolerability at single doses of 200 to 600 milliliters (0.09 mg/mL) and multiple daily doses over one week without toxic reactions or plasma accumulation. Astragalus membranaceus extract preparations containing astragaloside IV as a standardized marker compound are registered in the Chinese Pharmacopoeia and are widely used in clinical practice in China, Japan, and the Republic of Korea for cardiovascular, hepatic, and immune-support indications. The telomerase-activating metabolite cycloastragenol is the active principle of the commercial nutraceutical TA-65, which has produced positive telomere-lengthening results in randomized controlled trials in middle-aged and older adults.

    This monograph documents the chemistry, biosynthesis, and structural characterization of astragaloside IV; the multi-target molecular pharmacology across NF-kB, Nrf2, PI3K/Akt, TGF-beta1/Smad, TLR4, and telomerase pathways; the pharmacokinetic profile including the critical gut-microbial biotransformation to cycloastragenol; the preclinical evidence base across cardiovascular, neurological, hepatic, renal, pulmonary, metabolic, and oncological models; the limited clinical evidence; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event and safety data; and a comparative assessment of five structurally or functionally related triterpenoid saponins against astragaloside IV on five competency standards.

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  • 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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  • Canagliflozin

    Selective sodium-glucose cotransporter 2 (SGLT2) inhibitor with secondary SGLT1 inhibitory activity

    A thiophene-containing C-glucoside developed by Mitsubishi Tanabe Pharma and licensed to Janssen as the first SGLT2 inhibitor approved in the United States, distinguished by dual SGLT2/SGLT1 inhibition and landmark cardiovascular and renal outcomes evidence from the CANVAS Program and CREDENCE trial.

    Abstract

    Canagliflozin is a potent, orally bioavailable inhibitor of the sodium-glucose cotransporter 2 (SGLT2) and the first agent of its class to receive United States Food and Drug Administration approval for the treatment of type 2 diabetes mellitus. The compound acts through an insulin-independent mechanism by blocking the reabsorption of filtered glucose in the proximal tubule of the kidney, producing sustained glycosuria, reduction in plasma glucose, modest body weight loss, and reduction in systolic blood pressure. Structurally, canagliflozin is a C-glucoside bearing a thiophene ring in the aglycone region, conferring metabolic stability against glucosidase cleavage and contributing to oral bioavailability of approximately 65 percent. The inhibition constant for human SGLT2 is approximately 4.2 nM, with approximately 160-fold to 250-fold selectivity over SGLT1 (Ki approximately 710 to 910 nM), a selectivity ratio that permits modest intestinal SGLT1 inhibition at the 300 mg clinical dose, contributing to postprandial glucose lowering through delayed intestinal glucose absorption [1, 2].

    The compound was discovered at Mitsubishi Tanabe Pharma through systematic optimization of C-glucoside scaffolds for SGLT2 potency, metabolic stability, and oral pharmacokinetics [1]. Janssen Pharmaceuticals obtained development and commercialization rights through a licensing agreement and advanced canagliflozin through a comprehensive Phase 3 program (nine controlled studies, approximately 10,285 subjects) culminating in FDA approval on 29 March 2013 under the trade name Invokana [3, 4]. The compound was subsequently approved by the European Medicines Agency in November 2013 and in multiple additional jurisdictions. A fixed-dose combination with metformin (Invokamet) was approved in 2014.

    The clinical evidence base for canagliflozin extends substantially beyond glycemic control. The CANVAS Program (Canagliflozin Cardiovascular Assessment Study and CANVAS-R; N = 10,142; mean follow-up 188.2 weeks), published by Neal et al. in the New England Journal of Medicine in 2017, demonstrated a statistically significant 14 percent reduction in the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (hazard ratio 0.86; 95 percent confidence interval 0.75 to 0.97) [5]. The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; N = 4,401; median follow-up 2.62 years), published by Perkovic et al. in the New England Journal of Medicine in 2019, demonstrated a 30 percent reduction in the primary composite of end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death (hazard ratio 0.70; 95 percent confidence interval 0.59 to 0.82), establishing canagliflozin as the first SGLT2 inhibitor with a dedicated positive renal outcomes trial [6].

    Pharmacokinetics are characterized by rapid oral absorption (time to peak 1 to 2 hours), dose-proportional exposure across a wide range (50 to 1600 mg), steady-state attainment within 4 to 5 days, and predominant elimination through hepatic O-glucuronidation by UGT1A9 and UGT2B4, producing two inactive metabolites (M5 and M7) [7]. The terminal elimination half-life is approximately 10.6 to 13.1 hours at steady state, supporting once-daily dosing. Approximately 60 percent of the administered dose is recovered in feces and 33 percent in urine. Clinically significant drug-drug interactions are limited; UGT enzyme inducers (rifampin, phenytoin, ritonavir) reduce canagliflozin exposure and may require dose adjustment.

    The safety profile includes class-related adverse events: genital mycotic infections (principally vulvovaginal candidiasis in women and balanitis in men; occurring in approximately 10 to 12 percent of patients), urinary tract infections, volume depletion events related to osmotic diuresis, and euglycemic diabetic ketoacidosis (rare but clinically significant). The CANVAS Program identified a signal for increased lower-extremity amputations (6.3 versus 3.4 per 1,000 patient-years; hazard ratio 1.97), predominantly at the toe and metatarsal level, prompting an FDA boxed warning in 2017 that was subsequently removed in 2020 after additional data, including the CREDENCE trial, did not confirm the excess risk at a comparable magnitude [5, 8]. Bone fracture risk was identified in CANVAS but not confirmed in CREDENCE. Fournier gangrene (necrotizing fasciitis of the perineum) has been reported rarely across the SGLT2 inhibitor class.

    This monograph documents the chemistry, synthesis, and structure-activity relationships of canagliflozin; the molecular pharmacology of SGLT2 and SGLT1 inhibition; the comprehensive human pharmacokinetic record; preclinical pharmacology in animal models of diabetes and kidney disease; the clinical evidence base across glycemic, cardiovascular, and renal outcomes; sourcing and quality verification for research applications; reconstitution and handling; stack-interaction considerations; adverse-event signal including the amputation and ketoacidosis findings; and a structured comparative assessment of five SGLT2 inhibitor alternatives (dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin, and bexagliflozin) against canagliflozin on five competency standards: novelty, effect size, promising potential, side-effect profile, and overall validation.

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  • Hemantane

    Aminoadamantane derivative with low-affinity noncompetitive NMDA receptor antagonism, selective MAO-B inhibition, and dopaminergic modulation

    An aminoadamantane-class antiparkinsonian agent developed at the Zakusov Institute of Pharmacology in Russia, distinguished from amantadine and memantine by a hexamethylenimine substituent that confers a broader pharmacological spectrum encompassing NMDA receptor channel blockade, selective monoamine oxidase B inhibition, dopamine transporter modulation, and anti-inflammatory activity.

    Abstract

    Hemantane (N-(2-adamantyl)hexamethyleneimine hydrochloride; gimantan) is an experimental antiparkinsonian and neuroprotective agent of the aminoadamantane structural class, synthesized and developed at the V.V. Zakusov Research Institute of Pharmacology of the Russian Academy of Medical Sciences. The compound shares the adamantane cage scaffold with the clinically established agents amantadine and memantine but is distinguished by the attachment of a seven-membered azepane (hexamethylenimine) ring at the 2-position of the adamantane nucleus, a modification that broadens the pharmacological profile relative to the parent aminoadamantanes. Hemantane acts through multiple convergent mechanisms: it is a low-affinity, noncompetitive (uncompetitive) open-channel blocker of the N-methyl-D-aspartate (NMDA) subtype of the ionotropic glutamate receptor; a weak, competitive, selective inhibitor of monoamine oxidase B (MAO-B; Ki approximately 470 micromolar); a noncompetitive modulator of the dopamine transporter (DAT) that acutely reduces striatal dopamine reuptake Vmax by approximately 30 percent; a modulator of dopamine receptor subtype density (upregulating D1 and downregulating D2/D3 binding sites in the striatum after subchronic administration); and a putative sigma receptor agonist. The compound also exhibits anti-inflammatory activity in models of peripheral inflammation (acetic acid peritonitis, carrageenan-induced paw edema) and in a lipopolysaccharide-induced neuroinflammation model of Parkinson disease, where it attenuated weight loss, contralateral forepaw akinesia, and olfactory behavioral disruption.

    In preclinical parkinsonism models, hemantane (10 to 20 mg/kg intraperitoneally) reduced tremor, rigidity, and oligokinesia, and was reported to be superior to the reference drug amantadine in several behavioral paradigms. In the MPTP-treated C57BL/6 mouse model, subchronic hemantane administration increased dopamine transporter levels in multiple brain structures, a response broader than that produced by amantadine. A single administration of hemantane (20 mg/kg) in C57BL/6 mice reduced striatal DOPA concentration, decreased serotonin and its metabolite levels in the striatum, and altered the homovanillic acid to dopamine ratio in the frontal cortex, demonstrating modulatory activity across both dopaminergic and serotonergic systems.

    Clinical evaluation of hemantane has been conducted in a randomized, double-blind, placebo-controlled Phase 2 trial in 60 patients with newly diagnosed, untreated early-stage Parkinson disease over 16 weeks. Hemantane at 50 mg daily (25 mg twice daily) produced a 41 percent reduction in rigidity from baseline and statistically significant improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III motor examination scores at weeks 8, 12, and 16 compared with placebo. The 25 mg daily dose produced moderate efficacy. Safety monitoring (blood pressure, electrocardiogram, blood and urine parameters) did not identify dose-limiting toxicity at either dose. Additional preclinical research has demonstrated analgesic activity in somatic and visceral pain models, efficacy in reducing ethanol consumption in alcohol-experienced rats, attenuation of morphine withdrawal signs, and anti-arthritic activity when applied as a 5 percent topical gel formulation. The compound has not received marketing authorization in any jurisdiction and remains an investigational agent. This monograph documents the chemistry, synthesis, multi-target pharmacology, preclinical and clinical evidence, sourcing considerations, and a comparative assessment of hemantane against five structurally or mechanistically related compounds on five competency standards.

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