Author: kodiac

  • Atosiban

    Competitive oxytocin receptor and vasopressin V1a receptor antagonist (cyclic nonapeptide tocolytic)

    A synthetic cyclic nonapeptide analogue of oxytocin developed by Ferring Pharmaceuticals as a selective tocolytic for the management of preterm labor, distinguished from beta-adrenergic and calcium channel blocker tocolytics by its uterine-specific mechanism of action and favorable maternal cardiovascular safety profile.

    Abstract

    Atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin; CAS 90779-69-4; molecular formula C43H67N11O12S2; molecular weight 994.19 g/mol) is a synthetic cyclic nonapeptide analogue of oxytocin that functions as a competitive antagonist at the oxytocin receptor and at the vasopressin V1a receptor, developed by Ferring Pharmaceuticals in Sweden and first reported in the literature by Melin et al. in 1986 [1]. The compound is the only oxytocin receptor antagonist approved for clinical tocolytic use, registered in the European Union since January 2000 under the trade name Tractocile and subsequently approved in approximately 67 countries for the acute management of preterm labor in pregnant women between 24 and 33 completed weeks of gestation. Atosiban is not approved by the United States Food and Drug Administration or in Japan; the absence of United States registration reflects Ferring’s assessment that the FDA requirement for placebo-controlled trials in United States patients would be ethically untenable rather than a formal regulatory rejection on efficacy or safety grounds [2]. At the molecular level, atosiban inhibits oxytocin-mediated activation of the Gq/phospholipase C/inositol 1,4,5-trisphosphate signaling cascade in myometrial cells, reducing intracellular calcium release from the sarcoplasmic reticulum and diminishing calcium influx through voltage-gated channels, thereby suppressing uterine smooth muscle contraction [3, 4]. The compound additionally suppresses oxytocin-mediated prostaglandin E2 and prostaglandin F2-alpha release from decidual tissue, a secondary mechanism that contributes to the tocolytic effect. Receptor binding studies report moderate affinity for the oxytocin receptor (Ki approximately 397 nmol/L) and high affinity for the vasopressin V1a receptor (Ki approximately 4.7 nmol/L), with negligible affinity at the V1b and V2 vasopressin receptor subtypes [5]. The onset of uterine quiescence after intravenous administration is rapid, with significant reduction in contraction frequency within 10 minutes. Pharmacokinetics are characterized by an initial half-life of 0.21 hours and a terminal half-life of 1.7 hours after intravenous infusion, a volume of distribution of 18.3 liters, plasma protein binding of 46 to 48 percent in pregnant women, and predominantly peptidase-mediated metabolism that is independent of the cytochrome P450 system [6]. The standard clinical dosing regimen comprises a 6.75 mg intravenous bolus followed by a loading infusion of 300 micrograms per minute for 3 hours and a maintenance infusion of 100 micrograms per minute for up to 45 hours, with total treatment not exceeding 48 hours and total dose not exceeding 330.75 mg. Phase III clinical trials demonstrated that 59.6 percent of atosiban-treated women remained undelivered without alternative tocolysis at 7 days compared to 47.7 percent in the beta-agonist comparator arm, with maternal cardiovascular adverse events occurring approximately 10-fold less frequently in the atosiban group (8.3 percent versus 81.2 percent) [7, 8]. The compound is well tolerated; nausea is the most common adverse event at 14 percent, and no serious maternal safety signals have been identified across more than 156,000 treatment cycles in postmarketing surveillance through 2005. A secondary research application in assisted reproduction has emerged from the observation that atosiban-mediated reduction in uterine contractility during embryo transfer may improve implantation rates in in vitro fertilization, with meta-analyses reporting significantly higher clinical pregnancy rates in atosiban-treated groups compared to controls [9, 10]. This monograph documents the chemistry, synthesis, and peptide pharmacology of atosiban; the oxytocin receptor and vasopressin V1a receptor antagonism in molecular and functional detail; the comprehensive pharmacokinetic record; the clinical evidence base across tocolytic and assisted reproduction indications; sourcing and quality verification considerations for research-grade material; reconstitution and handling protocols; stack-interaction implications; adverse-event signal; and a structured comparative assessment of five alternative tocolytic agents (nifedipine, ritodrine, indomethacin, magnesium sulfate, terbutaline) against atosiban on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1357Open in new tab →

    Download PDF →

    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.

  • Glepaglutide

    Long-acting glucagon-like peptide-2 (GLP-2) receptor agonist peptide analog

    A 39-amino-acid synthetic peptide analog of human glucagon-like peptide-2 engineered by Zealand Pharma with nine amino acid substitutions and a C-terminal hexalysine tail to enable depot formation, extended half-life, and ready-to-use liquid formulation for subcutaneous administration in short bowel syndrome.

    Abstract

    Glepaglutide (ZP1848) is a long-acting, synthetic peptide analog of human glucagon-like peptide-2 (GLP-2) developed by Zealand Pharma A/S (Soeborg, Denmark) for the treatment of short bowel syndrome (SBS) with intestinal failure in patients dependent on parenteral support. The compound comprises 39 amino acids and differs from native human GLP-2(1-33) by the incorporation of nine amino acid substitutions at positions 2, 3, 5, 8, 10, 11, 16, 24, and 28, together with a C-terminal amidated hexalysine tail ([Lys]6-NH2) derived from Zealand Pharma’s proprietary Structure Inducing Probe (SIP) technology. The substitutions confer resistance to dipeptidyl peptidase-4 (DPP-4) degradation, improved physicochemical stability enabling a ready-to-use aqueous liquid formulation, and formation of a subcutaneous depot from which the parent compound and its active C-terminally truncated metabolites (M1, 35 amino acids; M2, 34 amino acids) are slowly released into systemic circulation. The resulting effective half-life of approximately 50 to 124 hours in humans permits twice-weekly or once-weekly subcutaneous dosing, a substantial advance over the daily injection requirement of teduglutide (Gattex), the first-in-class approved GLP-2 analog. Glepaglutide binds and activates the GLP-2 receptor (GLP-2R), a class B G-protein-coupled receptor expressed on intestinal subepithelial myofibroblasts, enteroendocrine cells, and enteric neurons. Receptor activation triggers downstream release of intestinal growth mediators including insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and keratinocyte growth factor, resulting in crypt cell proliferation, villus elongation, inhibition of enterocyte apoptosis, enhanced intestinal barrier function, increased mesenteric blood flow, and suppression of gastric acid hypersecretion and accelerated gastrointestinal motility. The net physiological effect is increased intestinal absorptive capacity for fluid, electrolytes, and macronutrients in patients with anatomically shortened bowel. Clinical development has progressed through Phase 1 healthy volunteer pharmacokinetic studies, a Phase 2 randomized crossover trial in 18 SBS patients published in The Lancet Gastroenterology and Hepatology (Naimi et al., 2019) demonstrating dose-dependent improvements in intestinal wet weight absorption and plasma citrulline, and the pivotal Phase 3 EASE-SBS 1 trial (NCT03690206), a multinational, double-blind, placebo-controlled study in 106 patients that met its primary endpoint of significant reduction in weekly parenteral support volume at 24 weeks (mean change minus 5.13 versus minus 2.85 liters per week for glepaglutide twice weekly versus placebo; P equals 0.0039). The compound received orphan drug designation from both the United States Food and Drug Administration and the European Medicines Agency. Zealand Pharma submitted a New Drug Application to the FDA in late 2023; in December 2024, the FDA issued a Complete Response Letter citing insufficient evidence to confirm efficacy and safety at the proposed marketed dose and recommending an additional confirmatory trial. A Marketing Authorization Application was submitted to the European Medicines Agency in June 2025, and Zealand Pharma plans an additional Phase 3 trial to support regulatory resubmission in the United States. The safety profile is consistent with the known GLP-2 class effects. The most frequent adverse events in clinical trials are injection site reactions, stoma complications (primarily swelling or enlargement of the stoma nipple), gastrointestinal events (nausea, vomiting, abdominal pain), peripheral edema, fatigue, and headache. Anti-drug antibodies develop in a proportion of treated patients with a trend toward higher injection site reaction incidence in antibody-positive individuals, though no firm causal relationship has been established. The compound does not require reconstitution and is administered as a fixed-dose, ready-to-use subcutaneous injection via autoinjector, representing a practical advantage over lyophilized GLP-2 analogs requiring daily preparation. This monograph documents the chemistry, design rationale, and synthesis of glepaglutide; the GLP-2 receptor pharmacology and downstream intestinotrophic signaling; the comprehensive human pharmacokinetic profile including depot formation and metabolite characterization; the preclinical pharmacology in intestinal growth and inflammatory bowel disease models; the clinical evidence base from Phase 1 through Phase 3; sourcing and quality verification; reconstitution and handling; stack interaction considerations; adverse events and safety signals; and a comparative assessment of five GLP-2 receptor agonist candidates (teduglutide, apraglutide, dapiglutide, elsiglutide, and native GLP-2) against glepaglutide on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1414Open in new tab →

    Download PDF →

    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.

  • Bradanicline

    Selective alpha-7 nicotinic acetylcholine receptor full agonist

    A quinuclidine benzofuran-2-carboxamide developed at Targacept as a selective alpha-7 nicotinic full agonist with a binding affinity of 1.4 nanomolar at the human alpha-7 receptor, advanced through Phase 2 development for cognitive impairment and negative symptoms of schizophrenia with a positive 12-week exploratory trial followed by a negative larger 24-week confirmatory trial, subsequently licensed to Anvylic Therapeutics for Tourette syndrome and other indications.

    Abstract

    Bradanicline (development codes TC-5619 and ATA-101) is a small-molecule, highly selective full agonist of the homopentameric alpha-7 subtype of the neuronal nicotinic acetylcholine receptor (alpha-7 nAChR), originated at Targacept Pharmaceuticals (Winston-Salem, North Carolina) from a quinuclidine benzofuran-2-carboxamide chemistry program in the mid-2000s and advanced through Phase 1 and Phase 2 clinical development for cognitive impairment associated with schizophrenia. The compound binds the human alpha-7 nicotinic receptor with a Ki of approximately 1.4 nanomolar, slightly higher affinity than encenicline (Ki approximately 4 nanomolar) and substantially higher affinity than tropisetron at the alpha-7 site, and exhibits functional intrinsic activity of approximately 80 to 90 percent of the acetylcholine maximum response in heterologous expression systems, placing it in the high-efficacy stratum of alpha-7 ligands as a full agonist rather than the partial-agonist class that encenicline and tropisetron occupy. The full-agonist intrinsic activity is the principal medicinal-chemistry differentiator of bradanicline within the broader quinuclidine-amide chemical class. Selectivity over alpha-4-beta-2, alpha-3-beta-4, alpha-3-beta-2, and other neuronal nicotinic subtypes is approximately 100-fold or greater. The compound was advanced through an exploratory Phase 2 trial in 185 schizophrenia patients (Lieberman et al. 2013) at 5 milligrams once daily for 12 weeks, with statistically significant improvement on the Groton Maze Learning Task and on the Scale for Assessment of Negative Symptoms compared to placebo, and a statistically significant drug effect on working memory in the tobacco-using subgroup. A larger confirmatory Phase 2 trial (Walling et al. 2016) in 477 schizophrenia outpatients across 64 sites at 5 or 50 milligrams once daily for 24 weeks did not support a benefit on negative or cognitive symptoms compared to placebo. Targacept terminated the cognitive impairment program in 2013 and the compound was subsequently licensed to Catalyst Biosciences and to Anvylic Therapeutics for Tourette syndrome and selected other neurological indications. The compound represents a useful research-clinical reference for the alpha-7 nicotinic full-agonist class and for the assessment of whether higher functional intrinsic activity at the receptor produces greater clinical benefit. Bradanicline did not produce the severe gastrointestinal toxicity that triggered the September 2015 FDA clinical hold on encenicline; the safety profile in Phase 2 was well-tolerated with no clinically noteworthy findings reported. The compound is supplied as a research-grade reagent (greater than 98 percent purity) by multiple chemical suppliers and continues to serve as a reference alpha-7 nicotinic full agonist for fundamental pharmacology research. This monograph reviews the chemistry, synthesis, and stereochemistry of bradanicline; the receptor pharmacology in detail; the human pharmacokinetic record; the indication-by-indication clinical evidence base; and a structured comparative assessment of five alpha-7 nicotinic acetylcholine receptor candidates against bradanicline on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1353Open in new tab →

    Download PDF →

    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.

  • Anamorelin

    Non-peptidic ghrelin receptor (GHSR-1a) agonist with orexigenic, anabolic, and growth hormone secretagogue activity

    A small-molecule peptidomimetic ghrelin receptor agonist developed from the Novo Nordisk growth hormone secretagogue program, approved in Japan for the treatment of cancer cachexia in non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer, and investigated in osteosarcopenia and other wasting conditions.

    Abstract

    Anamorelin (ONO-7643, RC-1291, ST-1291) is a non-peptidic, orally active, centrally penetrant agonist of the growth hormone secretagogue receptor type 1a (GHSR-1a), the endogenous receptor for ghrelin. Structurally derived from peptidomimetic optimization of the growth hormone-releasing peptide scaffold at Novo Nordisk and subsequently developed by Helsinn Healthcare and Ono Pharmaceutical, anamorelin binds the ghrelin receptor with subnanomolar affinity (Ki 0.70 nM) and produces full agonist activity in fluorescence imaging plate reader (FLIPR) calcium mobilization assays with an EC50 of 0.74 nM, comparable to endogenous ghrelin (Ki 0.58 nM, EC50 0.67 nM) [1]. No antagonist activity has been observed at concentrations up to 1000 nM. The compound is distinguished from endogenous ghrelin by oral bioavailability, a plasma elimination half-life of approximately 7 to 12 hours (compared to approximately 30 minutes for ghrelin), and the absence of peptidic instability. Pharmacodynamically, a single oral dose of 100 mg produces rapid and sustained elevation of circulating growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 3 (IGFBP-3), with secondary increases in appetite, caloric intake, and body weight observed on chronic dosing. The principal clinical application is cancer anorexia-cachexia syndrome (CACS). Two pivotal Phase 3 randomized, double-blind, placebo-controlled trials (ROMANA 1 and ROMANA 2), conducted in 979 patients with inoperable stage III or IV non-small cell lung cancer and cachexia across 93 sites in 19 countries, demonstrated that anamorelin 100 mg daily for 12 weeks significantly increased lean body mass (median change +1.10 kg versus -0.44 kg on placebo in ROMANA 1; +0.75 kg versus -0.96 kg in ROMANA 2; both P < 0.001) and body weight, with concurrent improvement in anorexia-cachexia symptoms and quality of life measures [2]. However, both trials failed to demonstrate statistically significant improvement in the co-primary endpoint of handgrip strength, a finding that became the basis for the European Medicines Agency refusal of marketing authorization in 2017 [3]. In Japan, where a separate Phase 2 trial (ONO-7643-04) in Japanese non-small cell lung cancer patients with cachexia and a Phase 3 open-label study (ONO-7643-05) in gastrointestinal cancer cachexia confirmed lean body mass and body weight increases, anamorelin received manufacturing and marketing approval from the Pharmaceuticals and Medical Devices Agency on December 11, 2020, as the first ghrelin receptor agonist approved worldwide for cancer cachexia [4]. It is marketed as Adlumiz tablets (50 mg) by Ono Pharmaceutical and has been available since April 2021 for the treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, or colorectal cancer. Pharmacokinetics are characterized by rapid oral absorption (time to peak concentration 0.5 to 2.0 hours), a pronounced food effect (4-fold reduction in area under the curve when administered with food), hepatic metabolism predominantly through cytochrome P450 3A4 (CYP3A4) with minor contributions from CYP2C8 and CYP2D6, and fecal excretion of approximately 92 percent of the administered dose [5, 6]. The CYP3A4 dependence produces clinically significant drug-drug interaction potential with strong CYP3A4 inhibitors (ketoconazole increases the AUC of anamorelin by approximately 4-fold). The compound depresses cardiac conduction and has sodium channel-blocking activity; prolongation of the PR interval, QRS complex, and QT interval has been observed in clinical trials, with a frequency of approximately 10.7 percent for conduction system abnormalities in Japanese registration studies [7, 8]. Contraindications include congestive heart failure, recent myocardial infarction or angina pectoris, and severe cardiac conduction defects. The most frequent adverse events are hyperglycemia (5 to 6 percent overall, substantially higher in patients with pre-existing diabetes), elevated gamma-glutamyl transpeptidase, and gastrointestinal symptoms. This monograph reviews the chemistry, synthesis, and structural pharmacology of anamorelin; the ghrelin receptor mechanism in molecular and physiological detail; comprehensive pharmacokinetics including food effect and CYP3A4 interaction; the preclinical pharmacology in rat, pig, and tumor xenograft models; the clinical evidence base across the ROMANA program, Japanese registration studies, and the osteosarcopenia indication; sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signals; and a comparative assessment of five cachexia and wasting treatment candidates (ibutamoren, enobosarm, megestrol acetate, mirtazapine, and espindolol) against anamorelin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1417Open in new tab →

    Download PDF →

    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.

  • Buserelin

    Synthetic gonadotropin-releasing hormone superagonist nonapeptide with paradoxical chronic suppression of pituitary-gonadal axis through GnRH receptor desensitization and downregulation

    A synthetic nonapeptide analog of endogenous gonadotropin-releasing hormone bearing a D-serine(tert-butyl) substitution at position 6 and an ethylamide C-terminal modification, conferring 20- to 170-fold greater potency than native GnRH and resistance to enzymatic degradation, developed at Hoechst AG in the mid-1970s as one of the first clinically viable GnRH superagonists and now registered in approximately 40 jurisdictions for hormone-dependent prostate cancer, endometriosis, uterine fibroids, premenopausal breast cancer, central precocious puberty, and pituitary downregulation in assisted reproduction protocols.

    Abstract

    Buserelin ([D-Ser(tBu)6,des-Gly-NH2-10]GnRH ethylamide; CAS 57982-77-1, free base; 68630-75-1, acetate salt) is a synthetic nonapeptide analog of the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH, also designated luteinizing hormone-releasing hormone, LHRH) first described by Sandow and colleagues at Hoechst AG in 1976 and approved for clinical use in 1984 [1, 2]. The compound incorporates two structural modifications to native GnRH that collectively confer superagonist potency and metabolic stability: replacement of glycine at position 6 with D-serine bearing a tert-butyl ether on the side-chain hydroxyl, which eliminates the principal endopeptidase cleavage site and introduces conformational rigidity favorable to receptor binding; and replacement of the C-terminal glycinamide (position 10) with an ethylamide, which further resists carboxypeptidase degradation. The resulting peptide binds the type I GnRH receptor with affinity approximately 20- to 170-fold greater than native GnRH and produces a biphasic pharmacological response that is the mechanistic foundation for all clinical applications [3, 4]. Acute administration stimulates pituitary gonadotroph secretion of luteinizing hormone and follicle-stimulating hormone, producing transient elevations in gonadal steroid output (the “flare” phase, lasting 7 to 14 days). Chronic continuous administration produces homologous desensitization of the GnRH receptor through receptor internalization, uncoupling from Gq/11-phospholipase C signaling, and transcriptional downregulation of GnRH receptor expression, resulting in profound and sustained suppression of gonadotropin secretion and a hypogonadal state equivalent to surgical castration in both sexes [5, 6]. This medical castration is reversible on cessation of treatment. Buserelin was the first GnRH agonist demonstrated to achieve medical castration in humans via intranasal administration, an observation reported by Sandow and colleagues in 1980 that established the clinical viability of non-injectable GnRH agonist therapy [2]. The compound is registered in approximately 40 jurisdictions across Europe, the United Kingdom, Canada, New Zealand, South Africa, Latin America, and Asia, but is not approved in the United States or Australia. Registered indications include hormone-responsive prostate cancer, endometriosis, uterine fibroids, premenopausal breast cancer, and pituitary downregulation as an adjunct to controlled ovarian hyperstimulation in assisted reproduction [7, 8, 9]. The compound is additionally used off-label for central precocious puberty and as a component of gender-affirming hormone therapy. Pharmacokinetics are characterized by negligible oral bioavailability due to gastrointestinal peptidase degradation, approximately 2.5 to 3.3 percent intranasal bioavailability, and approximately 70 percent subcutaneous bioavailability [10]. The plasma elimination half-life is 50 to 80 minutes after intravenous or subcutaneous administration and approximately 1 to 2 hours after intranasal dosing. Protein binding is low (approximately 15 percent). Metabolism occurs principally through pyroglutamyl peptidase and chymotrypsin-like endopeptidase activity in the liver, kidneys, and gastrointestinal tract, with approximately 50 percent of the administered dose recovered unchanged in urine [10, 11]. Formulations include aqueous solution for subcutaneous injection and intranasal spray (requiring multiple daily administrations) and sustained-release subcutaneous implants providing 2- or 3-month depot delivery. The adverse-event profile is dominated by the pharmacological consequences of gonadal steroid suppression: hot flashes, reduced libido, erectile dysfunction or vaginal dryness, and long-term bone mineral density reduction. The initial flare phase carries specific risk in metastatic prostate cancer (bone pain exacerbation, spinal cord compression, ureteral obstruction), which is mitigated clinically by co-administration of an antiandrogen during the first 2 to 4 weeks of therapy. This monograph reviews the chemistry and synthesis, the biphasic GnRH receptor pharmacology, the comprehensive human pharmacokinetic record, the clinical evidence base across prostate cancer, endometriosis, uterine fibroids, breast cancer, precocious puberty, and assisted reproduction indications, sourcing and quality verification, reconstitution and handling, stack interactions, adverse-event signal, and a comparative assessment of five GnRH agonist candidates against buserelin on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1395Open in new tab →

    Download PDF →

    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.

  • Teduglutide

    Dipeptidyl peptidase-IV-resistant glucagon-like peptide-2 analog and GLP-2 receptor agonist

    A recombinant 33-amino-acid analog of human glucagon-like peptide-2 bearing a single glycine-for-alanine substitution at position 2 that confers resistance to dipeptidyl peptidase-IV degradation, developed by NPS Pharmaceuticals and approved for the treatment of short bowel syndrome with intestinal failure in adults and pediatric patients dependent on parenteral support.

    Abstract

    Teduglutide is a recombinant analog of human glucagon-like peptide-2 (GLP-2) and the first GLP-2 receptor agonist approved for clinical use in the treatment of short bowel syndrome associated with intestinal failure (SBS-IF). The compound differs from native human GLP-2 by a single amino acid substitution: glycine replaces alanine at position 2 from the N-terminus, eliminating the dipeptidyl peptidase-IV (DPP-IV) cleavage site and extending the plasma elimination half-life from approximately 7 minutes (native GLP-2) to approximately 2 to 3 hours after subcutaneous administration [1, 2]. This modification preserves full agonist activity at the GLP-2 receptor (GLP-2R), a class B G-protein-coupled receptor expressed on intestinal subepithelial myofibroblasts, enteric neurons, and enteroendocrine cells, while enabling once-daily subcutaneous dosing at 0.05 mg/kg body weight.

    The intestinotrophic actions of teduglutide are mediated through GLP-2R activation on subepithelial myofibroblasts, which triggers downstream release of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and keratinocyte growth factor (KGF) [3, 4]. These paracrine mediators drive crypt cell proliferation, inhibit enterocyte apoptosis, increase villus height, enhance mucosal barrier function, slow gastric emptying, reduce gastric acid secretion, and increase mesenteric blood flow [5]. The composite physiological effect is an expansion of absorptive intestinal surface area and an improvement in the efficiency of fluid and nutrient absorption in patients with shortened bowel.

    Clinical development centered on the pivotal Phase 3 STEPS trial (Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent Short-Bowel Syndrome Subjects), in which 86 adult SBS-IF patients were randomized to teduglutide 0.05 mg/kg/day or placebo for 24 weeks [6]. The primary endpoint (20 to 100 percent reduction in parenteral support volume at weeks 20 and 24) was met by 63 percent of teduglutide-treated patients compared to 30 percent of placebo-treated patients (P = 0.002). Three teduglutide-treated patients achieved complete enteral autonomy (full independence from parenteral support). Long-term extension studies (STEPS-2, STEPS-3) demonstrated sustained reductions in parenteral support requirements over 30 months or more, with additional patients achieving enteral autonomy on continued treatment [7, 8].

    Teduglutide received European Commission marketing authorization as Revestive in August 2012, United States Food and Drug Administration (FDA) approval as Gattex in December 2012 for adult SBS-IF patients dependent on parenteral support, and FDA pediatric indication expansion in May 2019 for patients one year of age and older [9, 10]. The compound was developed by NPS Pharmaceuticals (subsequently acquired by Shire, then Takeda), with Takeda holding global commercial rights.

    The principal safety concerns are the trophic effects of sustained GLP-2R stimulation on intestinal epithelium. Colorectal polyps have been reported in clinical trials and postmarketing surveillance at rates higher than placebo, necessitating colonoscopy within 6 months before treatment initiation, after 1 year of treatment, and every 5 years thereafter [11]. Intestinal obstruction, biliary and pancreatic disease, and fluid overload from increased intestinal absorption are additional monitored risks. Common adverse events at the approved dose include abdominal pain (28 percent), nausea (26 percent), injection site reactions (26 percent), abdominal distension (17 percent), and headache (16 percent) [12].

    This monograph reviews the chemistry, amino acid sequence, and DPP-IV resistance mechanism of teduglutide; the discovery of GLP-2 as an intestinotrophic factor and the development trajectory from preclinical demonstration through registration; the molecular pharmacology of GLP-2R signaling and downstream trophic mediators; the pharmacokinetic profile including absorption, distribution, metabolism, and elimination; the preclinical evidence in rodent models of SBS, mucositis, and colitis; the clinical evidence base across the STEPS trial series and pediatric studies; sourcing and quality verification considerations; reconstitution and handling; stack interaction considerations including effects on oral medication absorption; the adverse event and safety profile with emphasis on colorectal polyp risk; and a comparative assessment of five alternative GLP-2R agonists or intestinal trophic agents (glepaglutide, apraglutide, native GLP-2, growth hormone with glutamine, and somatropin) against teduglutide on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1415Open in new tab →

    Download PDF →

    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.

  • Carbetocin

    Long-acting synthetic oxytocin receptor agonist with functional Gq selectivity

    A 1-deamino-1-monocarba analog of oxytocin developed by Ferring Pharmaceuticals as a heat-stable uterotonic for the prevention of postpartum hemorrhage, distinguished from native oxytocin by enzymatic resistance, prolonged duration of action, functional selectivity at the Gq signaling pathway, and investigational application in Prader-Willi syndrome hyperphagia.

    Abstract

    Carbetocin (1-deamino-1-monocarba-(2-O-methyltyrosine)-oxytocin; CAS 37025-55-1; molecular formula C45H69N11O12S; molecular weight 988.16) is a synthetic long-acting analog of the neurohypophysial peptide oxytocin, developed for the prevention of uterine atony and postpartum hemorrhage following cesarean and vaginal delivery. The compound incorporates two critical structural modifications relative to native oxytocin: replacement of the disulfide bridge with a thioether (monocarba) linkage that confers resistance to disulfide reductases, and deamination of the N-terminal cysteine residue that eliminates aminopeptidase-mediated degradation. These modifications extend the plasma elimination half-life from approximately 3 to 4 minutes (oxytocin) to approximately 40 to 85 minutes (carbetocin), producing sustained uterotonic activity from a single 100 microgram intravenous or intramuscular injection [1, 2]. Carbetocin acts as a selective agonist at the oxytocin receptor (OXTR), a class A G protein-coupled receptor expressed on myometrial smooth muscle, myoepithelial cells of the mammary gland, and neuronal populations in the hypothalamus, amygdala, and brainstem. Molecular pharmacology studies have characterized carbetocin as a functionally selective (biased) Gq agonist: it activates the Gq/phospholipase C/inositol trisphosphate signaling cascade with partial agonist efficacy while inducing receptor internalization through a beta-arrestin-independent pathway that prevents receptor recycling to the plasma membrane [3]. This functional selectivity profile distinguishes carbetocin from native oxytocin (which recruits both Gq and beta-arrestin pathways) and from vasopressin V1a/V1b receptors at which carbetocin shows negligible agonist activity. The compound was first approved in 1997 (Duratocin, Pabal; Ferring Pharmaceuticals) for prevention of uterine atony following cesarean delivery and is now registered in more than 80 countries. The World Health Organization CHAMPION trial (Widmer et al. 2018), a 29,645-patient multinational randomized noninferiority study, demonstrated that a heat-stable formulation of carbetocin (100 microgram intramuscular) was noninferior to oxytocin (10 IU intramuscular) for prevention of postpartum hemorrhage after vaginal birth, establishing the compound as a viable alternative in settings where cold-chain storage is unavailable [4]. A second clinical development program, advanced by Acadia Pharmaceuticals, has evaluated intranasal carbetocin (3.2 to 9.6 mg three times daily) for the treatment of hyperphagia, anxiousness, and distress behaviors in Prader-Willi syndrome (PWS); the CARE-PWS Phase 3 trial (Kimonis et al. 2023) reported clinically meaningful improvements in hyperphagia at the 3.2 mg dose in 130 participants aged 7 to 18 years [5, 6]. Pharmacokinetics after intravenous administration show biphasic elimination with a terminal half-life of approximately 33 minutes; intramuscular administration produces a terminal half-life of approximately 55 minutes with bioavailability exceeding 80 percent [7]. The compound is well tolerated at registered doses; principal adverse events are nausea, vomiting, abdominal pain, flushing, headache, and transient hypotension, with a safety profile comparable to or more favorable than standard-dose oxytocin in pooled meta-analytic data [8, 9]. This monograph reviews the chemistry, synthesis, and structural modifications of carbetocin; the biased receptor pharmacology at the oxytocin receptor; comprehensive human pharmacokinetics; preclinical uterotonic and neurobehavioral pharmacology; the clinical evidence base across postpartum hemorrhage prevention and Prader-Willi syndrome indications; sourcing and quality verification considerations for research applications; reconstitution and handling; stack-interaction implications; adverse-event signal; and a comparative assessment of five alternative uterotonics and oxytocin-system compounds against carbetocin on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1394Open in new tab →

    Download PDF →

    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.

  • Cardiogen

    Synthetic cardioprotective tetrapeptide bioregulator with epigenetic gene-regulatory and anti-apoptotic activity targeting cardiomyocytes

    A synthetic tetrapeptide (H-Ala-Glu-Asp-Arg-OH; AEDR) developed at the Saint Petersburg Institute of Bioregulation and Gerontology as an ultrashort peptide bioregulator with cardioprotective, anti-apoptotic, and epigenetic chromatin-regulatory activity targeting cardiomyocytes, cardiac fibroblasts, and myocardial gene expression programs.

    Abstract

    Cardiogen (H-Ala-Glu-Asp-Arg-OH; AEDR tetrapeptide; molecular formula C18H31N7O9; molecular weight 489.48 g/mol) is a synthetic tetrapeptide bioregulator developed by Vladimir Khavinson and colleagues at the Saint Petersburg Institute of Bioregulation and Gerontology as the cardiac-specific member of the Khavinson ultrashort peptide bioregulator family [1, 2]. The compound belongs to a class of synthetic two-to-seven-residue peptide sequences modeled on tissue-specific peptide fragments isolated from mammalian organ extracts, and is designated as the cardiovascular system bioregulator within this peptide family. Cardiogen shares the Ala-Glu-Asp tripeptide core with the cortical bioregulator Cortagen (Ala-Glu-Asp-Pro) and the pineal bioregulator Epithalon (Ala-Glu-Asp-Gly), differing from these compounds by the fourth-position arginine residue, a single amino acid substitution that determines cardiac tissue specificity within the Khavinson classification system [3, 4]. The principal molecular mechanism of Cardiogen, characterized through molecular modeling, cell culture, and organotypic myocardial tissue studies, is epigenetic regulation of gene expression through direct interaction of the tetrapeptide with double-stranded DNA in gene promoter regions and with histone proteins (H1, H2B, H3, H4), producing chromatin decondensation and reactivation of transcriptional programs in cardiac cells [5, 6, 7]. The cardioprotective activity, characterized in organotypic myocardial tissue cultures, embryonic fibroblast cultures, and coronary artery ligation animal models, includes stimulation of cardiomyocyte proliferation with concurrent suppression of cardiomyocyte apoptosis through p53 protein downregulation, upregulation of cytoskeletal proteins (actin, vimentin, tubulin) by up to five-fold and nuclear matrix proteins (lamin A, lamin C) by up to 2.5-fold relative to control, preservation of myocardial glycogen stores and cellular energy production structures under ischemic conditions, and a reported threefold reduction in mortality following experimental coronary artery ligation in treated versus control groups [8, 9, 10, 11]. In a separate line of investigation, Cardiogen demonstrated tumor-modifying activity against transplanted M-1 sarcoma in senescent rats, with dose-dependent inhibition of tumor growth mediated by hemorrhagic necrosis and stimulation of tumor cell apoptosis through a vascular mechanism rather than direct cytostatic effect [12]. The compound has been characterized in the context of the senescence-associated secretory phenotype of cardiovascular system cells and inflammaging, with evidence that the AEDR tetrapeptide regulates molecules involved in the inflammatory pathways contributing to age-related cardiovascular decline [13]. No formal pharmacokinetic studies have been published for Cardiogen as the isolated synthetic AEDR tetrapeptide. As a linear tetrapeptide with unprotected termini, the compound is expected to undergo rapid proteolytic degradation by aminopeptidases and carboxypeptidases in plasma and gastrointestinal fluid; however, molecular modeling studies have demonstrated that ultrashort peptides are substrates of the proton-coupled oligopeptide transporter (PEPT1/PEPT2) family carriers, supporting intestinal absorption and cellular uptake through active transport mechanisms [14, 15]. No human clinical trials have been published. The compound is not approved by the United States Food and Drug Administration, the European Medicines Agency, or any major Western regulatory authority. Cardiogen is registered in the Russian Federation as a biologically active additive and is commercially available there in capsule and sublingual formulations. It is supplied internationally as a research-grade lyophilized peptide by multiple peptide synthesis vendors at greater than 95 percent purity by high-performance liquid chromatography. This monograph reviews the chemistry, synthesis, and structural characterization of Cardiogen; the discovery and development history within the Khavinson bioregulatory peptide program; the molecular pharmacology including peptide-DNA binding, histone interaction, and cardiac gene expression modulation; the pharmacokinetic considerations for ultrashort peptides; the preclinical pharmacology across cardiac, inflammatory, and aging cell models; the clinical evidence base (absent); sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signal; and a comparative assessment of five cardioprotective or cardiac-repair peptide candidates (Vesugen, Thymosin beta-4, BPC-157, Cortagen, GHK-Cu) against Cardiogen on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1402Open in new tab →

    Download PDF →

    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.

  • Spexin

    Endogenous neuropeptide agonist of galanin receptor type 2 (GALR2) and galanin receptor type 3 (GALR3)

    A 14-amino-acid C-terminally amidated neuropeptide of the galanin/kisspeptin/spexin superfamily, identified by bioinformatic hidden Markov model screening of the human proteome in 2007 and subsequently characterized as a satiety factor, metabolic regulator, anxiolytic peptide, and antinociceptive agent operating through selective activation of galanin receptor subtypes 2 and 3.

    Abstract

    Spexin (SPX), also designated neuropeptide Q (NPQ), is a 14-amino-acid peptide hormone encoded by the C12orf39 gene on human chromosome 12 and processed from a 116-amino-acid prepropeptide by dibasic cleavage and C-terminal alpha-amidation [1, 2]. The mature human sequence (NWTPQAMLYLKGAQ-NH2) is perfectly conserved across all mammalian species examined and differs by only one to two residues from teleost orthologs, placing spexin among the most evolutionarily conserved vertebrate peptide hormones [3]. First identified in 2007 by Mirabeau and colleagues through a hidden Markov model algorithm designed to detect novel secreted peptide hormones in the human genome, and first confirmed biochemically in murine esophageal and gastric tissue [1], spexin was subsequently shown to activate galanin receptor type 2 (GALR2) and galanin receptor type 3 (GALR3) with nanomolar potency (EC50 values of approximately 45.7 and 112.2 nM respectively) while showing no measurable activity at galanin receptor type 1 (GALR1) [4, 5]. This receptor selectivity profile distinguishes spexin from galanin itself, which activates all three galanin receptor subtypes, and establishes spexin as a naturally occurring GALR2/GALR3-selective agonist. The peptide is expressed broadly across central and peripheral tissues including the hypothalamus, hippocampus, amygdala, adipose tissue, liver, gastrointestinal tract, pancreas, kidney, heart, ovary, and testis [6, 7]. Functionally, spexin has been characterized as a satiety factor that suppresses food intake in goldfish, zebrafish, and mice through hypothalamic regulation of orexigenic (neuropeptide Y, agouti-related protein) and anorexigenic (proopiomelanocortin, cocaine- and amphetamine-regulated transcript) neuropeptides [8, 9, 10]. In adipose tissue, spexin inhibits long-chain fatty acid uptake into adipocytes and promotes weight loss in diet-induced obese rodents [11]. Circulating spexin concentrations are significantly reduced in human obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, and polycystic ovary syndrome, establishing the peptide as a candidate biomarker for metabolic dysregulation [12, 13, 14]. Beyond metabolic regulation, spexin-based GALR2-selective agonists produce anxiolytic effects in murine behavioral models [5], and the metabolically stabilized analog LIT-01-144 produces potent non-opioid peripheral antinociception in persistent inflammatory pain through GALR2 activation [15]. In reproductive physiology, spexin inhibits gonadotropin (LH and FSH) synthesis and secretion in multiple vertebrate species and negatively regulates ovarian steroidogenesis [16, 17]. No human clinical trials of exogenous spexin administration have been reported; the compound remains in the preclinical and biomarker research phase. This monograph reviews the chemistry, gene structure, and peptide processing of spexin; the receptor pharmacology and signal transduction through GALR2 and GALR3; the preclinical pharmacology across metabolic, appetite, nociceptive, anxiolytic, reproductive, and cardiovascular domains; the human biomarker and associative clinical evidence; sourcing and handling considerations for research-grade material; analog development for metabolic stability; and a comparative assessment against five related peptide or receptor-targeted candidates on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1387Open in new tab →

    Download PDF →

    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.

  • Somatropin

    Recombinant human growth hormone (191-amino acid single-chain polypeptide, identical to endogenous pituitary 22 kDa growth hormone)

    A 191-amino acid recombinant polypeptide identical to endogenous pituitary-derived 22 kDa human growth hormone, produced by recombinant DNA technology in Escherichia coli or Saccharomyces cerevisiae, indicated for growth hormone deficiency across pediatric and adult populations and distinguished from earlier pituitary-extracted preparations by the elimination of prion contamination risk and by the capacity for unlimited supply.

    Abstract

    Somatropin is the International Nonproprietary Name for recombinant human growth hormone (rhGH), a 191-amino acid, single-chain, non-glycosylated polypeptide with a molecular weight of 22,124 daltons that is identical in primary sequence to the major circulating isoform of endogenous pituitary growth hormone encoded by the GH1 gene on chromosome 17q23.3. The compound was first produced by recombinant DNA technology at Genentech, Inc., where Goeddel et al. (1979) achieved direct expression of the human GH coding sequence in Escherichia coli [1], leading to the FDA approval of somatrem (methionyl-hGH, Protropin) in 1985 and of somatropin (authentic 191-amino acid sequence, Humatrope) in 1987. The transition from cadaveric pituitary-extracted growth hormone to recombinant production was driven by the identification in 1985 of Creutzfeldt-Jakob disease cases in recipients of pituitary-derived GH, a transmissible spongiform encephalopathy that resulted in the withdrawal of all pituitary-derived GH preparations worldwide [2, 3]. Somatropin acts through the growth hormone receptor (GHR), a single-pass transmembrane receptor of the type I cytokine receptor superfamily. Ligand binding induces receptor dimerization and rotational activation, transphosphorylation of the receptor-associated tyrosine kinase Janus kinase 2 (JAK2), and downstream activation of signal transducer and activator of transcription 5b (STAT5b), the mitogen-activated protein kinase (MAPK/ERK) cascade, and the phosphatidylinositol 3-kinase/Akt pathway [4, 5]. The dominant endocrine mediator of the growth-promoting action of somatropin is insulin-like growth factor 1 (IGF-1), synthesized principally in the liver in response to GH receptor activation and acting through the IGF-1 receptor on growth plate chondrocytes, skeletal muscle, and other target tissues [6]. Pharmacokinetics after subcutaneous injection are characterized by an absorption half-life of approximately 2 to 3 hours, a peak plasma concentration at 3 to 6 hours, a systemic bioavailability of approximately 70 to 80 percent, a volume of distribution approximating plasma volume (approximately 50 mL/kg), and an elimination half-life of 3 to 5 hours driven predominantly by renal and hepatic receptor-mediated clearance [7, 8]. Approved indications in the United States and the European Union include pediatric growth hormone deficiency, Turner syndrome, chronic renal insufficiency prior to transplantation, Prader-Willi syndrome, children born small for gestational age who fail to demonstrate catch-up growth, idiopathic short stature, SHOX gene haploinsufficiency, Noonan syndrome, adult growth hormone deficiency, and AIDS-associated wasting and cachexia [9, 10]. The compound is administered by daily subcutaneous injection at weight-based doses typically in the range of 0.024 to 0.067 mg/kg/day in pediatric indications and 0.1 to 0.8 mg/day (non-weight-based) in adult GH deficiency, with dose titration guided by serum IGF-1 concentration [10, 11]. Long-acting formulations including somapacitan (Sogroya, weekly subcutaneous) and lonapegsomatropin (Skytrofa, weekly subcutaneous) have been approved since 2020 as alternatives to daily somatropin for selected indications [12, 13]. The principal adverse events are dose-dependent and include peripheral edema, arthralgia, myalgia, carpal tunnel syndrome, and insulin resistance, all attributable to the physiological actions of growth hormone on sodium retention, connective tissue, and glucose metabolism [14]. Long-term safety surveillance through multinational registries (KIGS, GeNeSIS, HypoCCS, NCGS) encompassing more than 100,000 patient-years has not demonstrated a causal increase in de novo malignancy, recurrence of primary tumors, or cardiovascular mortality at replacement doses, though the data mandate continued vigilance in patients with active malignancy, proliferative diabetic retinopathy, or critical illness [15, 16, 17]. This monograph documents the chemistry and biosynthesis of somatropin; the growth hormone receptor signaling cascade in molecular detail; the comprehensive human pharmacokinetic record; the preclinical pharmacology of the GH-IGF-1 axis; the clinical evidence base across all approved and investigational indications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event and safety-signal analysis; and a comparative assessment of five alternative growth-promoting or GH-axis compounds against somatropin on five competency standards.

    Read the full monograph

    The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

    KDC-MN-1382Open in new tab →

    Download PDF →

    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.