Tag: MONOGRAPH

  • Ulotaront

    Plain-language summaryIntrigue 76 / 100

    Ulotaront (SEP-363856) was an exciting investigational antipsychotic from Sumitomo (Sunovion) that worked through a completely different mechanism than every other drug in its class: activation of the trace amine-associated receptor 1 (TAAR1) plus serotonin 5-HT1A activation, with no measurable activity at dopamine D2 or serotonin 5-HT2A receptors at all. The Phase 2 data published in the New England Journal of Medicine in 2020 generated significant enthusiasm, suggesting it might be the first non-D2 antipsychotic ever to reach approval. The Phase 3 DIAMOND trials read out in 2023 and failed to demonstrate efficacy versus placebo, which was a substantial disappointment for the field. The TAAR1 mechanism remains under active investigation by other companies. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Trace amine-associated receptor 1 (TAAR1) full agonist with serotonin 5-HT1A receptor partial agonism

    A first-in-class TAAR1/5-HT1A dual agonist discovered through phenotypic screening, developed for schizophrenia under FDA Breakthrough Therapy Designation, and distinguished from all approved antipsychotics by the absence of dopamine D2 and serotonin 5-HT2A receptor antagonism.

    Abstract

    Ulotaront (SEP-363856) is a thienopyran-based small molecule and the first trace amine-associated receptor 1 (TAAR1) agonist to reach Phase 3 clinical development for the treatment of schizophrenia. Discovered through a target-agnostic phenotypic screening collaboration between PsychoGenics and Sunovion Pharmaceuticals (now Sumitomo Pharma), ulotaront was identified using the SmartCube automated behavioral platform rather than rational design against TAAR1, and its molecular target was subsequently deconvoluted to reveal full agonism at human TAAR1 (EC50 approximately 38 to 140 nM, Emax approximately 101 to 109 percent) and partial agonism at the serotonin 5-HT1A receptor (EC50 approximately 2.3 micromolar, Emax approximately 75 percent). The compound is not an antagonist at either the dopamine D2 or the serotonin 5-HT2A receptor, the two canonical targets of all currently approved first-generation and second-generation antipsychotics. This mechanistic distinction positions ulotaront as a fundamentally novel pharmacological approach to psychotic disorders, with a preclinical and early clinical profile that suggests potential advantages in the avoidance of extrapyramidal symptoms, metabolic syndrome, hyperprolactinemia, and sedation that limit the tolerability of existing antipsychotic therapies.

    In preclinical models, ulotaront dose-dependently reduced phencyclidine-induced hyperlocomotion, restored prepulse inhibition deficits, increased social interaction in chronic phencyclidine paradigms, and ameliorated cognitive impairments, all without producing catalepsy at doses up to 100 mg/kg. The compound prevented olanzapine-induced weight gain in rodents and demonstrated no effect on prolactin release. Pharmacokinetics are characterized by rapid oral absorption, greater than 70 percent bioavailability in preclinical species, high blood-brain barrier penetration (brain concentrations approximately threefold higher than plasma), a median effective half-life of approximately 7 hours in humans supporting once-daily dosing, and predominant hepatic metabolism through CYP2D6. The compound received FDA Breakthrough Therapy Designation in May 2019 on the basis of a positive Phase 2 randomized controlled trial (Koblan et al., 2020) in 245 acutely psychotic adults with schizophrenia, in which ulotaront at 50 to 75 mg/day produced a statistically significant reduction in Positive and Negative Syndrome Scale (PANSS) total score of 17.2 points versus 9.7 points on placebo at four weeks (effect size 0.45, p less than 0.001), with concurrent improvement on negative symptom, depressive symptom, and global severity measures. A 26-week open-label extension demonstrated sustained improvement (PANSS total reduction of 41.8 points from double-blind baseline) with a favorable metabolic and movement disorder safety profile.

    The Phase 3 DIAMOND program, however, produced negative results. DIAMOND 1 (ulotaront 50 and 75 mg/day versus placebo in 435 patients) and DIAMOND 2 (ulotaront 75 and 100 mg/day versus placebo in 464 patients) both failed to meet their primary endpoints at six weeks, with large placebo responses potentially masking the therapeutic signal. Additional Phase 3 studies (DIAMOND 3, long-term extension, and a switch study versus quetiapine) were planned or ongoing at the time of the negative readouts. Despite the Phase 3 setback in schizophrenia, ulotaront continues in Phase 2/3 development for generalized anxiety disorder and as adjunctive therapy in major depressive disorder, reflecting the broader neuropsychiatric potential of the TAAR1 mechanism. This monograph reviews the chemistry, discovery, molecular pharmacology, comprehensive pharmacokinetics, preclinical and clinical evidence across all studied indications, sourcing and handling considerations, stack interactions, adverse events, and a comparative assessment of five alternative approaches to non-dopaminergic antipsychotic pharmacology against ulotaront 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.

  • Carnosic-Acid

    Phenolic abietane diterpene with pro-electrophilic Nrf2/Keap1 pathway activation and pleiotropic antioxidant, anti-inflammatory, and neuroprotective activity

    A catechol-type abietane diterpene isolated from Rosmarinus officinalis and Salvia officinalis, distinguished by a pro-electrophilic mechanism of Nrf2 activation through oxidative conversion to a quinone intermediate that S-alkylates Keap1 cysteine residues, conferring context-dependent neuroprotective, anti-inflammatory, and cytoprotective activity selectively in tissues under oxidative stress.

    Abstract

    Carnosic acid is the principal lipophilic phenolic diterpene of rosemary (Salvia rosmarinus, formerly Rosmarinus officinalis) and common sage (Salvia officinalis), constituting approximately 1.5 to 5 percent of dried leaf mass and serving as the primary bioactive antioxidant constituent of commercial rosemary extracts designated E392 in European food-additive regulations. The compound belongs to the abietane diterpenoid structural class and is characterized by a catechol (ortho-dihydroxybenzene) moiety on ring C of the phenanthrene skeleton that confers both direct radical-scavenging activity and, more distinctively, pro-electrophilic activation of the Keap1/Nrf2/ARE cytoprotective transcriptional pathway. Under conditions of oxidative stress, the catechol ring of carnosic acid undergoes two-electron oxidation to an ortho-quinone electrophile that forms covalent thioether adducts with reactive cysteine residues (principally Cys151, Cys273, and Cys288) on the Keap1 sensor protein, releasing the transcription factor Nrf2 from proteasomal degradation and permitting its nuclear translocation and transactivation of antioxidant response element (ARE)-driven phase 2 genes including heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and thioredoxin reductase 1. This pro-electrophilic mechanism is pharmacologically significant because it renders the compound conditionally active: carnosic acid is converted to its electrophilic effector form preferentially in tissues experiencing elevated reactive oxygen species flux, thereby concentrating cytoprotective gene induction at sites of pathological oxidative damage rather than systemically. The neuroprotective activity of carnosic acid has been characterized in multiple rodent models of neurodegeneration and neuroinflammation, including 6-hydroxydopamine and MPTP models of Parkinson’s disease, middle cerebral artery occlusion models of ischemic stroke, controlled cortical impact models of traumatic brain injury, and transgenic mouse models of Alzheimer’s disease (5xFAD). In the 5xFAD model, a diacetyl pro-drug derivative (diAcCA) with improved oral stability and approximately 20 percent greater bioavailability than the parent compound reduced amyloid plaque burden, suppressed microglial and astrocytic inflammatory gene expression, and normalized spatial and working memory at oral doses translating to feasible human-equivalent exposures. Beyond neuroprotection, carnosic acid has demonstrated preclinical anti-inflammatory activity through suppression of NF-kappaB signaling and reduction of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) in models of colitis, hepatotoxicity, periodontitis, and high-fat-diet-induced neuroinflammation; antiproliferative and pro-apoptotic activity against multiple cancer cell lines (melanoma, glioma, breast, prostate, colon, renal, esophageal) through modulation of PI3K/AKT/mTOR, MAPK, and STAT3 signaling pathways; hepatoprotective activity against acetaminophen-induced and carbon-tetrachloride-induced liver injury; and antiadipogenic activity through PPARgamma modulation. Pharmacokinetically, carnosic acid is orally bioavailable (approximately 40 to 65 percent in rodent models), undergoes extensive hepatic phase II glucuronidation, and achieves measurable plasma concentrations in humans after oral administration of standardized rosemary extract. The oral median lethal dose in mice exceeds 7100 mg/kg, and 30-day repeated-dose toxicity studies at 150 mg/kg/day in rats produced no significant histopathological changes. The Joint FAO/WHO Expert Committee on Food Additives has established an acceptable daily intake of 0 to 0.6 mg/kg body weight per day for carnosic acid and carnosol combined. Human clinical data remain limited; no registration trials have been completed for any therapeutic indication, and the compound is not approved as a medicine by any regulatory authority. This monograph reviews the chemistry, natural occurrence, and isolation of carnosic acid; the pro-electrophilic Nrf2/Keap1 mechanism in molecular detail; the pharmacokinetic record including absorption, distribution, metabolism, and elimination; the preclinical pharmacology across neuroprotective, anti-inflammatory, anticancer, and hepatoprotective domains; the limited clinical evidence base; sourcing and quality verification; reconstitution and handling; stack interactions; adverse-event and safety signal; and a comparative assessment of five alternative Nrf2-activating or rosemary-derived compounds against carnosic acid 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.

  • MK-8722

    Direct pan-activator of AMP-activated protein kinase (AMPK) binding the allosteric drug and metabolite (ADaM) site

    A potent, orally bioavailable, direct allosteric pan-AMPK activator developed at Merck Research Laboratories that produces insulin-independent skeletal muscle glucose uptake across species but whose clinical translation was precluded by on-mechanism cardiac hypertrophy and glycogen accumulation in preclinical chronic dosing studies.

    Abstract

    MK-8722 is a potent, direct, orally bioavailable allosteric activator of all twelve mammalian heterotrimeric complexes of AMP-activated protein kinase (AMPK), the master cellular energy sensor that coordinates catabolic and anabolic metabolic pathways in response to energetic stress. Discovered at Merck Research Laboratories through a medicinal chemistry optimization campaign starting from the thienopyridone lead series and published in two landmark reports (Myers et al., Science, 2017; Feng et al., ACS Medicinal Chemistry Letters, 2018), MK-8722 binds the allosteric drug and metabolite (ADaM) site at the interface of the alpha-subunit kinase domain and the beta-subunit carbohydrate-binding module and produces dose-dependent activation of AMPK complexes containing both the beta-1 and beta-2 regulatory subunits.

    The pharmacological consequence of systemic pan-AMPK activation by MK-8722 in preclinical species is a robust, durable, insulin-independent increase in skeletal muscle glucose uptake and glycogen synthesis, with resultant improvements in whole-body glycemia and glucose tolerance in lean and obese rodent models and in spontaneously diabetic rhesus monkeys. The glucose-lowering effect is mediated predominantly through AMPK-dependent translocation of glucose transporter type 4 (GLUT4) to the sarcolemma in skeletal muscle and does not produce hypoglycemia at efficacious doses. Positron emission tomography with [18F]fluorodeoxyglucose ([18F]FDG-PET) confirmed increased skeletal muscle glucose uptake in both rodents and non-human primates following MK-8722 administration. Pharmacokinetic properties in preclinical species supported once-daily oral dosing for chronic studies.

    The principal liability that precluded clinical advancement of MK-8722 was on-mechanism cardiac hypertrophy and cardiac glycogen accumulation observed during chronic dosing in both rodent and non-human primate models. In Sprague-Dawley rats, 4-week oral administration at doses achieving efficacious plasma exposures produced dose-dependent increases in heart weight and left ventricular wall thickness. In rhesus monkeys, 8-week oral administration produced similar cardiac hypertrophy with increased cardiac glycogen content. Echocardiographic assessment demonstrated preserved systolic and diastolic function despite the structural remodeling, and the cardiac hypertrophy appeared partially reversible on drug washout at the highest dose levels, though lower doses did not demonstrate full regression during the studied washout period. No arrhythmias or functional cardiac impairment were detected. The cardiac hypertrophy was attributed to pan-AMPK activation in cardiomyocytes, where AMPK-driven glucose uptake and glycogen synthesis produced pathological glycogen accumulation analogous to the phenotype observed in glycogen storage cardiomyopathy associated with activating mutations in the PRKAG2 gene encoding the AMPK gamma-2 subunit.

    MK-8722 has not entered human clinical trials. The compound remains an important pharmacological tool for the study of systemic AMPK activation in metabolic disease and a reference standard for structure-activity relationship studies in the ADaM-site AMPK activator class. A selectivity screen against 115 enzymes, transporters, and receptors identified modest off-target activity at the serotonin 5-HT2A receptor (Ki approximately 2.8 micromolar) and three additional targets at 3 to 10 micromolar, none of which are anticipated to produce pharmacologically significant effects at AMPK-relevant exposures. This monograph reviews the chemistry, synthesis, and stereochemistry of MK-8722; the molecular pharmacology of AMPK activation through the ADaM site; the preclinical pharmacokinetic and pharmacodynamic profile; the cardiac safety signal; sourcing and quality verification for research applications; reconstitution and handling; stack-interaction considerations for combination studies; adverse-event characterization; and a structured comparative assessment of five alternative AMPK activators against MK-8722 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.

  • Bacteriostatic-Water

    Preserved sterile aqueous vehicle for parenteral reconstitution and dilution

    A sterile, nonpyrogenic preparation of Water for Injection preserved with 0.9 percent benzyl alcohol, serving as the standard multi-dose diluent and reconstitution vehicle for lyophilized peptides, proteins, and small-molecule injectables in pharmaceutical, compounding, and research applications.

    Abstract

    Bacteriostatic Water for Injection, USP is a sterile, nonpyrogenic aqueous preparation containing 0.9 percent (9 mg/mL) benzyl alcohol as a bacteriostatic preservative, manufactured to the United States Pharmacopeia monograph specification and distributed under FDA oversight as a pharmaceutical-grade parenteral vehicle. Unlike Sterile Water for Injection, which contains no antimicrobial agent and is designated for single-use applications, Bacteriostatic Water for Injection is formulated specifically for multi-dose access, permitting repeated aseptic puncture of a single vial over a period of up to 28 days while maintaining microbiological integrity. The preparation is classified as a pharmaceutical vehicle rather than an active pharmaceutical ingredient; it carries no intrinsic therapeutic activity and is indicated exclusively as a diluent or solvent for drugs intended for intravenous, intramuscular, or subcutaneous injection, according to the labeling of the drug to be administered.

    The bacteriostatic property of the formulation derives entirely from the benzyl alcohol excipient, a simple aromatic primary alcohol (C6H5CH2OH; CAS 100-51-6; molecular weight 108.14 g/mol) that exerts its antimicrobial effect principally through disruption of bacterial cell membrane phospholipid bilayer integrity and interference with cellular metabolic processes. The mechanism is bacteriostatic rather than bactericidal: at 0.9 percent concentration, benzyl alcohol inhibits the reproduction of common environmental contaminants (including Staphylococcus aureus and Pseudomonas aeruginosa) without achieving immediate sterilization of the solution. This distinction is operationally important, as the formulation depends on initial sterility at the point of manufacture and on aseptic technique during use to maintain the sterile state; the preservative serves as a secondary barrier against microbial proliferation following vial puncture.

    Benzyl alcohol is metabolized in adult humans through a well-characterized hepatic oxidation pathway: alcohol dehydrogenase converts benzyl alcohol to benzaldehyde, aldehyde dehydrogenase converts benzaldehyde to benzoic acid, and benzoic acid is conjugated with glycine in the liver to form hippuric acid, which is excreted renally. Within six hours of oral administration of 1.5 g of benzyl alcohol, adult subjects excreted 75 to 85 percent of the dose as urinary hippuric acid, reflecting the efficiency of this metabolic pathway in mature individuals. However, in neonates (particularly premature infants), the enzymatic capacity for benzoic acid metabolism is developmentally immature, and repeated parenteral exposure to benzyl alcohol at cumulative doses of 100 to 240 mg/kg/day has been associated with a severe toxicity syndrome characterized by metabolic acidosis, gasping respirations, central nervous system depression, intraventricular hemorrhage, and cardiovascular collapse, termed the “gasping syndrome.” This association, first reported in 1982 in the New England Journal of Medicine and subsequently confirmed by the FDA, resulted in a regulatory contraindication against the use of benzyl alcohol-containing preparations in neonatal patients.

    The preparation is supplied in multi-dose glass or plastic flip-top vials, most commonly in a 30 mL presentation. The principal FDA-listed manufacturer is Hospira, Inc. (a Pfizer subsidiary), with the product distributed under NDC codes including 0409-3977. The USP monograph specifies a pH range of 4.5 to 7.0, a bacterial endotoxin limit of less than 0.5 USP Endotoxin Units per mL, and compliance with USP particulate matter, sterility, and container-closure integrity requirements. The preparation is isotonically and osmotically insufficient on its own and is not suitable for direct intravenous administration without prior dilution or reconstitution with the intended drug product; the tonicity of the final solution depends on the solute.

    This monograph reviews the compound identification, history, molecular pharmacology (of the benzyl alcohol preservative), pharmacokinetics of benzyl alcohol, the preclinical and clinical evidence base for safety and toxicology, sourcing and quality verification considerations, reconstitution and handling protocols, interactions with peptide and protein solutes, the adverse event and safety signal profile (including neonatal contraindication), and a comparative assessment of five alternative parenteral vehicles against Bacteriostatic Water for Injection 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.

  • CB-03-01

    Topical steroidal androgen receptor antagonist with peripherally selective antiandrogen activity

    A synthetic pregnane steroid developed by Cosmo Pharmaceuticals (Cassiopea) as a topically applied, peripherally selective androgen receptor antagonist for the treatment of acne vulgaris and androgenetic alopecia, distinguished from systemic antiandrogens by rapid local metabolism to inactive cortexolone and minimal systemic bioavailability.

    Abstract

    CB-03-01 (clascoterone; cortexolone 17alpha-propionate; 11-deoxycortisol 17alpha-propionate) is a synthetic pregnane steroid that functions as a competitive antagonist of the androgen receptor (AR) with submicromolar potency (IC50 approximately 0.4 to 1 micromolar in AR transactivation assays) and peripheral selectivity conferred by rapid enzymatic hydrolysis to the inactive parent compound cortexolone (11-deoxycortisol) in human skin, plasma, and hepatic tissue. The compound was identified from a structure-activity series of cortexolone 17alpha-monoesters screened for topical antiandrogen activity in the hamster flank organ test, in which CB-03-01 demonstrated potency approximately four times greater than progesterone, three times greater than flutamide, two times greater than finasteride, and approximately equivalent to cyproterone acetate, while lacking systemic antiandrogenic, antianabolic, or glucocorticoid activity after subcutaneous administration in rats. The molecular pharmacology centers on competitive displacement of dihydrotestosterone (DHT) from the androgen receptor in sebocytes and dermal papilla cells, resulting in suppression of androgen-responsive gene transcription, reduction of sebaceous lipid synthesis, inhibition of inflammatory cytokine production (including interleukin-6), and attenuation of androgen-driven miniaturization of scalp hair follicles. In human dermal papilla cell cultures, CB-03-01 demonstrated significantly greater inhibition of DHT-stimulated IL-6 synthesis than the direct AR antagonist enzalutamide.

    The compound received its first regulatory approval from the United States Food and Drug Administration in August 2020 as a 1% topical cream (Winlevi) for the treatment of acne vulgaris in patients aged 12 years and older, representing the first new mechanism of action approved for acne in approximately 40 years and the first topical antiandrogen approved for acne in any jurisdiction. Two pivotal Phase 3 randomized, double-blind, vehicle-controlled trials enrolling a total of 1440 patients with moderate to severe facial acne demonstrated statistically significant treatment success rates (Investigator Global Assessment score of 0 or 1 with at least a two-grade reduction) of approximately 18 to 20 percent for clascoterone versus 7 to 9 percent for vehicle at 12 weeks, with concurrent reductions in both inflammatory and noninflammatory lesion counts. Long-term safety data through 12 months demonstrated a favorable tolerability profile dominated by local application site reactions (erythema, dryness, pruritus) without clinically meaningful systemic antiandrogen effects.

    A second clinical program in androgenetic alopecia (AGA) has advanced through Phase 2 dose-ranging studies (2.5%, 5%, and 7.5% solutions applied twice daily) demonstrating statistically significant improvements in target area hair count (TAHC) at 6 and 12 months, and into Phase 3 registration trials (SCALP-1 and SCALP-2) using a 5% topical solution in 1465 male patients with mild to moderate AGA. The Phase 3 topline results reported statistically significant improvements in TAHC relative to vehicle, with a 5.39-fold relative improvement in one study and a 1.68-fold relative improvement in the second, the divergence attributable to baseline hair count differences rather than inconsistent drug performance. The safety profile in the AGA trials was comparable to vehicle, with no evidence of systemic androgen blockade.

    Pharmacokinetics following topical application are characterized by minimal systemic absorption. At maximal clinical use conditions (6 grams of 1% cream applied twice daily), steady-state plasma concentrations of clascoterone average 3.1 plus or minus 1.9 ng/mL with Cmax values of 4.5 plus or minus 2.9 ng/mL. The compound is rapidly hydrolyzed in plasma to cortexolone, which is detectable at concentrations generally near or below the lower limit of quantitation (0.5 ng/mL). Plasma protein binding is 84 to 89 percent. The principal safety signal is reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, observed in approximately 7 percent of adolescent and adult subjects in maximal-use pharmacokinetic studies, with all cases resolving within 4 weeks of discontinuation. This monograph reviews the chemistry, synthesis, and structural pharmacology of CB-03-01; the competitive androgen receptor antagonist mechanism in molecular detail; the pharmacokinetic profile including systemic absorption, metabolism, and HPA axis considerations; the preclinical pharmacology in hamster, rat, and human tissue models; the clinical evidence base across acne and androgenetic alopecia indications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal; and a comparative assessment of five alternative antiandrogen or androgen-modulating agents against CB-03-01 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.

  • Livagen

    Synthetic tetrapeptide bioregulator with hepatoprotective, epigenetic chromatin-remodeling, and enkephalinase-inhibitory activity

    A Khavinson-class synthetic tetrapeptide (Lys-Glu-Asp-Ala) developed at the St. Petersburg Institute of Bioregulation and Gerontology as a liver-targeted bioregulator, distinguished by its capacity to induce chromatin decondensation in aged cells, inhibit enkephalin-degrading enzymes in human serum, and restore hepatocyte protein synthesis in senescent tissue.

    Abstract

    Livagen (Lys-Glu-Asp-Ala; single-letter code KEDA) is a synthetic tetrapeptide bioregulator developed by Vladimir Khavinson and colleagues at the St. Petersburg Institute of Bioregulation and Gerontology as a liver-targeted member of the broader Khavinson short-peptide bioregulator family. The compound is characterized by three principal pharmacological activities studied across cell culture, animal, and limited human research: (1) epigenetic chromatin remodeling through induction of deheterochromatinization of pericentromeric structural heterochromatin and facultative heterochromatin in lymphocytes and hepatocytes from aged organisms, with consequent reactivation of ribosomal genes and euchromatic loci silenced during aging; (2) potent inhibition of enkephalin-degrading serum peptidases (IC50 approximately 20 micromolar), exceeding the inhibitory potency of established peptidase inhibitors including puromycin, leupeptin, and D-phenylalanyl-alanyl-arginine-p-nitroanilide, without direct interaction with mu or delta opioid receptors; and (3) restoration of protein synthesis rhythms and metabolic function in hepatocyte cultures from aged rats to levels characteristic of young animals at nanomolar concentrations.

    The chromatin-remodeling mechanism has been demonstrated in cultured lymphocytes from human subjects aged 75 to 88 years, in which Livagen induced activation of ribosomal genes, decondensation of pericentromeric heterochromatin of chromosomes 1, 9, and 16, and release of genes repressed through age-related condensation of euchromatic regions. This deheterochromatinization effect is shared with other Khavinson bioregulator peptides (Vilon, Epitalon, Cortagen) but appears tissue-preferential for hepatic and lymphoid lineages at the concentrations studied. Molecular modeling studies of the broader Khavinson peptide class suggest that short peptides interact with the nucleosome, histone proteins, and double-stranded DNA through steric and electrostatic complementarity, altering histone modification patterns and the accessibility of regulatory regions to transcription factors.

    In experimental models of liver pathology (acute and chronic hepatitis, liver fibrosis), the KEDA tetrapeptide demonstrated hepatoprotective and immunoprotective effects including normalization of total bilirubin, cholesterol, alanine aminotransferase, and aspartate aminotransferase levels; stimulation of tissue repair; and decreased destructive dystrophic processes in liver stroma. The maximal hepatoprotective effect was observed in aged animals, consistent with the bioregulator hypothesis that these peptides primarily restore age-depleted signaling. In aged rat hepatocyte cultures, Livagen restored circahoralian rhythms of protein synthesis to patterns characteristic of young specimens at nanomolar concentrations. A separate line of investigation demonstrated that oral administration of Livagen for two weeks modulated digestive enzyme activity in rats in an age-dependent manner, reducing enzyme activity in young animals while increasing it in old animals toward levels observed in young controls.

    The compound is resistant to hydrolysis by small intestinal peptidases and is not degraded to a measurable extent by the peptide hydrolases of the small intestine. Formal pharmacokinetic characterization meeting Western regulatory standards has not been published. The compound is not approved by any major Western regulatory authority (FDA, EMA) and is not registered on ClinicalTrials.gov. The primary research literature originates from Russian and Georgian institutions, and independent Western replication of key findings remains limited. This monograph reviews the chemistry, epigenetic pharmacology, hepatoprotective and digestive enzyme evidence, the limited pharmacokinetic record, sourcing and quality considerations, and a comparative assessment of five alternative hepatoprotective or epigenetic bioregulator compounds against Livagen 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.

  • Afobazole

    Plain-language summaryIntrigue 68 / 100

    Afobazole is a Russian anxiolytic that works through sigma-1 and other receptors rather than the GABA system. It is approved in Russia for generalized anxiety without sedation or dependence. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Selective non-benzodiazepine anxiolytic with sigma-1 receptor chaperone agonism and multi-target neuroprotective activity

    A 2-mercaptobenzimidazole derivative developed at the V.V. Zakusov Research Institute of Pharmacology and registered in Russia as a non-sedating anxiolytic, distinguished from benzodiazepines by absence of dependence liability and from buspirone by sigma-1 receptor chaperone agonism as the principal molecular mechanism.

    Abstract

    Afobazole (INN fabomotizole; development code CM-346; CAS 173352-21-1) is a 2-mercaptobenzimidazole anxiolytic synthesized and pharmacologically characterized at the V.V. Zakusov Research Institute of Pharmacology of the Russian Academy of Medical Sciences under the direction of Academician S.B. Seredenin. The compound was registered in the Russian Federation in 2006 for the treatment of generalized anxiety disorder and adjustment disorders, and was assigned the International Nonproprietary Name fabomotizole by the World Health Organization in 2012. Structurally, afobazole is 5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole, a synthetic benzimidazole bearing a thioether-linked morpholine side chain and an ethoxy substituent on the aromatic ring. The molecular formula is C15H21N3O2S (free base, molecular weight 307.41 g/mol), and the compound is supplied pharmaceutically as the dihydrochloride salt (C15H23Cl2N3O2S, molecular weight 380.33 g/mol).

    The pharmacological profile of afobazole is multi-target. Radioligand binding studies have identified the sigma-1 receptor chaperone protein (Sigma1R; Ki approximately 5.9 micromolar), NRH:quinone reductase 2 (NQO2, also designated the MT3 melatonin binding site; Ki approximately 0.97 micromolar), monoamine oxidase A (MAO-A regulatory site; Ki approximately 3.6 micromolar), and the melatonin MT1 receptor (Ki approximately 16 micromolar) as the principal molecular targets [1, 2]. The sigma-1 receptor interaction is the best-characterized mechanism: afobazole acts as a Sigma1R agonist, promoting dissociation of the Sigma1R-BiP complex at the endoplasmic reticulum membrane and downstream modulation of calcium signaling, inositol 1,4,5-trisphosphate receptor function, and expression of neurotrophic factors including nerve growth factor and brain-derived neurotrophic factor [3, 4]. The anxiolytic effect is blocked by selective Sigma1R antagonists (BD-1047, NE-100) in rodent behavioral models, confirming the dependence of the therapeutic activity on Sigma1R engagement [5, 6]. Unlike benzodiazepines, afobazole does not produce sedation, myorelaxation, amnesia, tolerance, physical dependence, or withdrawal syndrome at therapeutic doses, a profile confirmed in both preclinical and clinical studies [7, 8].

    Pharmacokinetics are characterized by rapid oral absorption (Tmax approximately 0.85 hours), pronounced first-pass hepatic metabolism (oral bioavailability approximately 44 percent), and a short plasma elimination half-life (approximately 0.82 hours) [9]. Despite the short systemic half-life, the anxiolytic effect persists substantially beyond the plasma residence of the parent compound, a pharmacodynamic feature attributed to the slow dissociation kinetics of the Sigma1R chaperone complex and to the sustained expression of downstream neurotrophic mediators. The recommended therapeutic dose is 30 mg per day in three divided administrations of 10 mg, with clinical effect emerging after 5 to 7 days of continuous dosing and maximal effect at 4 weeks [8, 10].

    The clinical evidence base comprises several Russian multicenter trials. The principal registration study was a randomized, double-blind, active-controlled trial of 150 patients with generalized anxiety disorder or adjustment disorders comparing afobazole (30 mg/day) to diazepam (30 mg/day) for 30 days; afobazole produced greater reduction in Hamilton Anxiety Rating Scale total score than diazepam (mean difference 2.93 points; p = 0.01), with 15 adverse events in the afobazole group versus 199 in the diazepam group, and no withdrawal syndrome on discontinuation [8]. Additional studies have evaluated afobazole in somatoform disorders, irritable bowel syndrome, premenstrual syndrome, alcohol withdrawal, and tobacco cessation, with consistent evidence of anxiolytic efficacy and favorable tolerability [10, 11, 12].

    Preclinical research has extended the pharmacological profile well beyond anxiolysis. Afobazole produces Sigma1R-dependent neuroprotection in rat models of ischemic stroke (middle cerebral artery occlusion), with reduced infarct volume and improved neurological outcomes when administered up to 24 hours post-occlusion [13, 14]. In the 6-hydroxydopamine mouse model of Parkinson’s disease, afobazole at 2.5 mg/kg intraperitoneally for 14 days restored striatal dopamine content, preserved tyrosine hydroxylase-positive neurons in the substantia nigra, and normalized motor coordination; these effects were abolished by the Sigma1R antagonist BD-1047 [15, 16]. Cardioprotective activity has been demonstrated in models of isoproterenol-induced myocardial injury, chronic heart failure, and alcoholic cardiomyopathy, with attenuation of pathological remodeling, preserved inotropic function, and reduced brain natriuretic peptide levels [17, 18, 19]. Angiogenic effects have also been reported [20].

    This monograph reviews the chemistry, synthesis, and structural class of afobazole; the multi-target molecular pharmacology with emphasis on the Sigma1R chaperone mechanism; the comprehensive pharmacokinetic profile; the preclinical pharmacology across anxiolytic, neuroprotective, cardioprotective, and anti-inflammatory models; the clinical evidence base in anxiety and related disorders; sourcing and quality considerations; reconstitution and handling; stack interactions; adverse events and safety signal; and a comparative assessment of five non-benzodiazepine anxiolytic candidates (buspirone, hydroxyzine, pregabalin, etifoxine, selank) against afobazole on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation). The compound is not approved by the United States Food and Drug Administration or the European Medicines Agency. It is registered in the Russian Federation and is available as an over-the-counter pharmaceutical product within that jurisdiction and as a research-grade preparation from international chemical suppliers.

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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.

  • Spermidine

    Plain-language summaryIntrigue 76 / 100

    Spermidine is a small natural polyamine found in wheat germ, aged cheese, and other foods. It induces autophagy (the cellular cleanup process) and has been linked to longevity in multiple species. Often sold as a longevity supplement. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Naturally occurring triamine polyamine and caloric restriction mimetic with autophagy-inducing, cardioprotective, and geroprotective activity

    An endogenous polyamine present in all eukaryotic cells, distinguished among geroprotective candidates by physiological autophagy induction via EP300 acetyltransferase inhibition, eIF5A hypusination, and epidemiologically validated cardiovascular and cognitive protection in aging populations.

    Abstract

    Spermidine (N-(3-aminopropyl)butane-1,4-diamine) is a naturally occurring triamine polyamine present in all living cells and in the human diet, principally from wheat germ, soybeans, fermented foods, and aged cheeses. First observed as a crystalline component of human semen by Antonie van Leeuwenhoek in 1678, spermidine was structurally characterized in the early twentieth century and subsequently identified as a central metabolite in polyamine biosynthesis, formed by the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine to putrescine by the enzyme spermidine synthase. The compound participates in multiple essential cellular processes including chromatin structure modulation, translational regulation through hypusination of eukaryotic translation initiation factor 5A (eIF5A), cell proliferation, and the induction of macroautophagy.

    The geroprotective potential of spermidine was established in a series of investigations beginning with the Eisenberg et al. (2009) demonstration that exogenous spermidine extends chronological lifespan in yeast, nematodes, and flies through autophagy-dependent mechanisms [1]. The molecular basis for autophagy induction was subsequently characterized as inhibition of the acetyltransferase EP300 (p300), resulting in hypoacetylation of core autophagy proteins (ATG5, ATG7, ATG12, and LC3) and convergent deacetylation of cytoplasmic proteins that parallels the acetylproteome shifts produced by caloric restriction and by other caloric restriction mimetics [2, 3]. Spermidine thereby occupies a mechanistically distinct position among autophagy inducers: it acts through acetyltransferase inhibition rather than through mTOR suppression (rapamycin), AMPK activation (metformin), or sirtuin activation (resveratrol).

    The landmark Eisenberg et al. (2016) study in Nature Medicine demonstrated that oral spermidine supplementation extends lifespan in mice, reduces cardiac hypertrophy, preserves diastolic function in aged animals, delays progression to heart failure in salt-sensitive hypertensive rats, and enhances cardiac autophagy, mitophagy, and mitochondrial respiration in an ATG5-dependent manner [4]. Epidemiological analysis of the Bruneck Study cohort (n = 829, 20-year follow-up) within the same report identified a significant inverse association between dietary spermidine intake and cardiovascular mortality, all-cause mortality, and cancer-related mortality, with the highest-intake tertile exhibiting a risk reduction comparable to approximately 5.7 years of aging [4, 5]. These findings were extended by Kiechl et al. (2018), who confirmed the inverse relationship between dietary spermidine and mortality in a larger epidemiological analysis [5].

    Clinical investigation of spermidine has advanced through several randomized controlled trials. The SmartAge trial (Wirth et al. 2018, 2022) evaluated spermidine-rich wheat germ extract supplementation in older adults with subjective cognitive decline; a 3-month pilot study reported modest memory improvement, while a 12-month Phase IIb trial did not demonstrate significant modification of memory performance or biomarkers at the studied dose [6, 7]. The POLYCAD trial (NCT05128331), a Danish randomized double-blind placebo-controlled study of 24 mg/day spermidine in 187 elderly patients with coronary artery disease, completed enrollment in 2025 and represents the first dedicated cardiovascular outcomes trial for spermidine [8]. Additional trials have examined metabolic responses to spermidine supplementation (NCT05459961) and dose-escalation safety in aging populations.

    Pharmacokinetic studies have revealed that dietary spermidine is rapidly absorbed from the intestinal lumen but is subject to extensive presystemic conversion to spermine, resulting in minimal elevation of circulating spermidine concentrations following oral supplementation at doses up to 40 mg/day [9, 10]. This observation suggests that the biological effects of oral spermidine may be mediated through local gastrointestinal and first-pass hepatic mechanisms, through polyamine interconversion in target tissues, or through modulation of gut microbiota-derived polyamine pools rather than through systemic plasma exposure.

    Spermidine supplementation has demonstrated a favorable safety profile in all completed human studies. No serious adverse events attributable to the compound have been reported. The European Food Safety Authority authorized spermidine-rich wheat germ extract as a Novel Food in 2021 with a recommended upper intake of 6 mg/day of spermidine [11]. Higher doses (up to 40 mg/day of purified spermidine for 28 days) have been evaluated without significant adverse effects in healthy older men [10]. This monograph reviews the chemistry, biosynthesis, and dietary sources of spermidine; the molecular pharmacology of autophagy induction, eIF5A hypusination, and anti-inflammatory signaling; pharmacokinetics; the preclinical and clinical evidence base across cardiovascular, cognitive, and geroprotective applications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse events and safety signal; and a comparative assessment of five geroprotective and autophagy-inducing compounds (rapamycin, resveratrol, nicotinamide mononucleotide, urolithin A, and metformin) against spermidine on five competency standards.

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  • BAM15

    Mitochondria-selective protonophore uncoupler of oxidative phosphorylation

    A synthetic oxadiazolopyrazine-scaffold mitochondrial protonophore distinguished from classical uncouplers by selective dissipation of the inner mitochondrial membrane proton gradient without depolarization of the plasma membrane, conferring potent metabolic enhancement with markedly reduced cytotoxicity in preclinical models of obesity, insulin resistance, hepatic steatosis, sepsis, and cancer.

    Abstract

    BAM15 (N5,N6-bis(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine) is a synthetic small-molecule mitochondrial protonophore first identified in a 2014 phenotypic screen by Kenwood et al. at the University of Virginia and Virginia Tech for compounds that uncouple mitochondrial oxidative phosphorylation without depolarizing the plasma membrane [1]. The compound dissipates the electrochemical proton gradient across the inner mitochondrial membrane, thereby uncoupling electron transport from adenosine triphosphate (ATP) synthesis and increasing substrate oxidation and energy expenditure. Unlike the classical protonophore uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP), BAM15 selectively targets the mitochondrial membrane and does not collapse the plasma membrane potential at effective uncoupling concentrations, a property that confers a substantially wider therapeutic index and reduced cytotoxicity in cultured cells and in vivo [1, 2]. The compound is orally bioavailable in mice (67 percent oral bioavailability, Cmax 8.2 micromolar, t1/2 1.7 hours) with primary distribution to the liver, supporting hepatic metabolic applications [3]. In C57BL/6J mice fed a high-fat diet, BAM15 administered at 100 mg/kg/day by oral gavage reversed diet-induced obesity, decreased body fat mass without altering food intake or lean body mass, reduced hepatic triglycerides by approximately 75 percent, decreased inflammatory lipids, and improved whole-body insulin sensitivity as demonstrated by hyperinsulinemic-euglycemic clamp [3]. In a head-to-head comparison in female db/db mice, BAM15 and calorie restriction improved body weight and liver steatosis to levels superior to semaglutide, niclosamide ethanolamine (NEN), and rosiglitazone, while BAM15, semaglutide, and rosiglitazone completely restored glucose tolerance [4]. These metabolic effects are mediated through sustained activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), promoting fatty acid oxidation, glucose uptake, and mitochondrial biogenesis [2, 5]. Beyond metabolic disease, BAM15 has demonstrated preclinical efficacy in acute kidney injury and sepsis (reducing mortality even when administered 12 hours after cecal ligation and puncture in mice) [6], in acute myeloid leukemia (inhibiting AML cell proliferation and inducing reactive oxygen species-mediated apoptosis with selectivity over normal cells) [7], in sarcopenic obesity (preserving skeletal muscle contractility and mitochondrial respiration in aged mice) [8, 9], in atherosclerosis (suppressing western diet-induced plaque formation in ApoE-knockout mice through AMPK activation and NF-kappaB/NLRP3 inflammasome suppression) [10, 11], and in vascular smooth muscle relaxation [5]. Safety pharmacology in rodents has demonstrated no alteration of body temperature, food intake, lean body mass, or standard hematological and biochemical markers of toxicity at effective metabolic doses [3]. BAM15 has not entered human clinical trials as of the most recent monograph revision. The compound is supplied as a research-grade material by multiple chemical suppliers at greater than 98 percent purity and is not approved by any regulatory authority for therapeutic use. This monograph documents the chemistry, synthesis, discovery history, molecular pharmacology, pharmacokinetics, preclinical evidence base across metabolic, inflammatory, oncologic, and aging indications, sourcing and quality verification, reconstitution and handling, stack-interaction considerations, adverse-event profile, and a structured comparative assessment against five alternative mitochondrial uncouplers.

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  • LM22A-4

    Small-molecule TrkB partial agonist and BDNF loop-domain mimetic

    A synthetic tris(hydroxyethyl) benzenetricarboxamide identified by in silico pharmacophore screening as a sub-nanomolar partial agonist of the TrkB neurotrophin receptor, distinguished by neuroprotective efficacy comparable to BDNF in rodent models of Huntington disease, Rett syndrome, traumatic brain injury, and demyelinating injury, with administration predominantly via the intranasal route owing to limited systemic blood-brain barrier penetration.

    Abstract

    LM22A-4, a synthetic 1-N,3-N,5-N-tris(2-hydroxyethyl)benzene-1,3,5-tricarboxamide of molecular weight 339.34 g/mol, is a small-molecule partial agonist of tropomyosin receptor kinase B (TrkB) originally identified in 2010 by Massa, Yang, Bhatt, and Longo through in silico pharmacophore screening of commercial chemical libraries against a model of the loop II domain of brain-derived neurotrophic factor (BDNF) [1]. The compound activates TrkB-dependent signaling cascades (phospho-TrkB, phospho-Akt, phospho-ERK1/2) in hippocampal and striatal neurons with a functional EC50 of 200 to 500 picomolar for TrkB activation and an IC50 of 47 nanomolar for competitive displacement of BDNF from the TrkB extracellular domain, producing neuronal survival at 80 to 90 percent of maximal BDNF efficacy in fetal hippocampal neuron assays [1]. The compound is approximately 98 percent smaller than the 27 kDa BDNF homodimer, is freely water-soluble, and is stable in aqueous solution at neutral pH, properties that make it operationally attractive as a research tool for investigating TrkB-dependent neurotrophic signaling in vitro and in vivo. A substantial preclinical literature, principally from the laboratories of Frank Longo and Stephen Massa at Stanford University and the University of California San Francisco, has demonstrated that LM22A-4 prevents neuronal degeneration with efficacy comparable to BDNF in multiple in vitro disease models, including amyloid-beta-induced hippocampal neuron death, MPP+-induced dopaminergic cell death (a Parkinson disease model), and quinolinic acid-induced striatal neuron death (a Huntington disease model) [1]. In vivo, LM22A-4 administered intranasally or by combined intraperitoneal and intranasal routes activates TrkB signaling in mouse hippocampus and striatum and produces functional benefit in rodent models of Huntington disease (R6/2 and BACHD transgenic mice) [2], Rett syndrome (MeCP2 mutant mice) [3, 4], pediatric and adult traumatic brain injury [5, 6], spinal cord injury [7], ischemic stroke [8], demyelinating injury (cuprizone model) [9], and nonarteritic anterior ischemic optic neuropathy [10]. The Huntington disease work by Simmons et al. (2013) demonstrated correction of striatal TrkB signaling deficits, reduction of intranuclear huntingtin aggregates, preservation of medium spiny neuron dendritic spine density, and improvement of motor function across both acute (R6/2) and chronic (BACHD) transgenic models at brain concentrations exceeding the in vitro neuroprotective dose [2]. The Rett syndrome work demonstrated acute reversal of spontaneous apneas and respiratory dysregulation in MeCP2-null and heterozygous mice, with 4-week treatment restoring wild-type breathing frequency and TrkB phosphorylation in medullary and pontine respiratory nuclei [3, 4]. A critical pharmacological limitation is poor blood-brain barrier penetration following systemic administration, which has necessitated intranasal delivery for central nervous system applications in essentially all published in vivo studies [1, 2]. The intranasal route bypasses the blood-brain barrier through olfactory and trigeminal nerve pathways, achieving cerebrospinal fluid and brain parenchymal concentrations sufficient for TrkB activation, but poses translational challenges for clinical development. A second limitation, identified by Bai et al. (2010) and extended by Todd et al. (2014) and subsequent investigations, is mechanistic complexity: multiplex quantitative assays suggest that LM22A-4 may not activate TrkB through direct orthosteric agonism but rather through indirect transactivation mediated by an unidentified G-protein coupled receptor and Src-family kinase (most likely Fyn) signaling [11, 12]. Despite this mechanistic debate, TrkB-dependence of the in vivo effects has been confirmed through conditional oligodendroglial TrkB deletion studies [9], and the functional neuroprotective and neuroregenerative outcomes are reproducible across laboratories and disease models. The compound has not entered human clinical trials as of the most recent monograph revision. It is supplied by multiple research chemical vendors at greater than 98 percent purity and is used exclusively as a research tool. This monograph reviews the chemistry, pharmacophore-based discovery, receptor pharmacology (including the transactivation controversy), pharmacokinetic limitations, the preclinical evidence base across all studied indications, sourcing and handling considerations, stack interactions, adverse-event signal, and a comparative assessment of five alternative TrkB/neurotrophin receptor ligands against LM22A-4 on five competency standards.

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