Capromorelin

Capromorelin (CP-424,391) is an orally active, non-peptide agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a, the ghrelin receptor) belonging to the pyrazolinone-piperidine dipeptide structural class. The compound was discovered at Pfizer Global Research and Development through systematic structure-activity optimization of peptidomimetic scaffolds and was selected as a clinical development candidate on the basis of high receptor affinity (Ki = 7 nM at human GHS-R1a), potent functional activity (EC50 = 3 nM in rat pituicyte growth hormone release assay), oral bioavailability, and robust in vivo growth hormone secretion in rodent and canine models [1, 2]. Capromorelin mimics the endogenous acylated peptide hormone ghrelin by binding the GHS-R1a receptor on somatotroph cells of the anterior pituitary gland and on hypothalamic neurons, activating Gq/11-coupled phospholipase C signaling, intracellular calcium mobilization, and consequent pulsatile growth hormone release through a pathway mechanistically distinct from and synergistic with the growth hormone releasing hormone (GHRH) receptor pathway. Secondary pharmacological activities include appetite stimulation through hypothalamic orexigenic circuits, transient elevation of circulating cortisol and prolactin, and sustained elevation of insulin-like growth factor 1 (IGF-1) on chronic dosing. In human clinical development, capromorelin advanced through Phase I single ascending dose studies in healthy volunteers and spinal cord injured patients (Ellis et al. 2015), demonstrating safety, tolerability, and dose-proportional pharmacokinetics at oral doses of 20 to 100 mg, and through a Phase II multicenter randomized placebo-controlled trial in 395 older adults aged 65 to 84 years with mild functional limitation (White et al. 2009), in which 12 months of daily oral capromorelin produced statistically significant increases in lean body mass (1.4 kg at 6 months, 1.6 kg at 12 months), growth hormone secretion, IGF-1 concentrations, and tandem stair climbing power compared to placebo [5, 6]. Human clinical development was subsequently discontinued; the compound did not advance to Phase III registration trials for age-related sarcopenia or functional decline. In veterinary medicine, capromorelin oral solution received United States Food and Drug Administration approval in 2016 as Entyce (Aratana Therapeutics, subsequently Elanco Animal Health) for appetite stimulation in dogs at an oral dose of 3 mg/kg once daily, and in October 2020 as Elura for the management of weight loss in cats with chronic kidney disease [7, 8, 9]. These veterinary approvals represent the only registered therapeutic applications of capromorelin as of the most recent monograph revision. The compound is the first and only FDA-approved ghrelin receptor agonist for appetite stimulation in companion animals and demonstrates the translational validity of the GHS-R1a mechanism for orexigenic and anabolic applications. Pharmacokinetics in dogs are characterized by rapid oral absorption (Tmax approximately 0.83 hours), moderate oral bioavailability (44 percent), hepatic metabolism predominantly through CYP3A4 and CYP3A5 mediated N-dealkylation and O-debenzylation, and a short terminal elimination half-life (approximately 1.2 hours in dogs, 2.4 hours in rats) [2, 15, 16]. In humans, single ascending oral doses of 20 to 100 mg produced dose-proportional increases in plasma concentration with broadly similar pharmacokinetic behavior between able-bodied and spinal cord injured participants [5]. The compound is well tolerated at studied doses; the principal adverse events across species are transient hypersalivation, mild emesis, loose stools, and transient increases in serum cortisol and glucose concentrations that normalize within hours of dosing. This monograph reviews the chemistry, synthesis, and structure-activity relationships of capromorelin; the GHS-R1a receptor pharmacology and downstream signaling; the comprehensive pharmacokinetic record across species; the preclinical pharmacology in rodent and canine models; the human clinical evidence base including Phase I and Phase II trials; the veterinary clinical evidence and regulatory approvals; sourcing and quality verification; reconstitution and handling; stack-interaction considerations for research applications; the adverse-event and safety profile; and a comparative assessment of five growth hormone secretagogue candidates (ibutamoren, anamorelin, macimorelin, ipamorelin, tabimorelin) against capromorelin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).