Tag: Selective androgen receptor modulator

ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) is a nonsteroidal selective androgen receptor modulator (SARM) identified in 2006 at ACADIA Pharmaceuticals AB through high-throughput screening employing receptor selection and amplification technology (R-SAT) and published in the Journal of Medicinal Chemistry in 2009 as the lead compound of a novel aryl nitrile series [1]. The compound binds the androgen receptor with high affinity (pEC50 of 9.0 at the wild-type human androgen receptor and 9.4 at the clinically relevant T877A mutant) and functions as a partial agonist relative to the full agonist activity of testosterone and dihydrotestosterone [1]. In vitro, ACP-105 is reported to be as potent as testosterone in androgen receptor functional assays without measurable interaction at other steroid hormone receptors, including estrogen, progesterone, glucocorticoid, and mineralocorticoid receptors. In vivo, in a two-week chronic study in castrated male rats, the compound improved anabolic parameters (levator ani muscle mass) at approximately 66 percent of the efficacy of testosterone while producing only approximately 21 percent of the androgenic stimulation of the prostate, yielding a favorable anabolic-to-androgenic dissociation ratio of approximately 3:1 [1, 2].

The compound crosses the blood-brain barrier with a reported brain-to-plasma ratio of 2.7, a property that has motivated investigation in central nervous system models [3, 4]. In a 2011 study by Dayger et al., subcutaneous administration of ACP-105 at 1 mg/kg/day to female C57BL/6J mice protected against 137-cesium irradiation-induced impairment of sensorimotor function on the rotarod and enhanced cued fear conditioning in both sham-irradiated and irradiated animals, with immunohistochemical evidence of region-specific modulation of microtubule-associated protein 2 (MAP-2) in the sensorimotor cortex [3]. In a 2013 study by George et al. in gonadectomized male triple-transgenic Alzheimer’s disease mice (3xTg-AD), ACP-105 at 10 mg/kg administered intraperitoneally four days per week reduced anxiety-like behavior when given alone and, when co-administered with the selective estrogen receptor beta agonist AC-186, improved long-term spatial memory on the Morris water maze, increased the amyloid-beta degrading enzymes neprilysin and insulin-degrading enzyme, and reduced brain amyloid-beta 40 and amyloid-beta 42 levels after seven months of treatment [4].

Predicted and in silico absorption, distribution, metabolism, and excretion (ADME) profiling indicates high gastrointestinal absorption (94 to 100 percent), moderate lipophilicity (LogP 3.0 to 3.5), strong plasma protein binding (77 to 99 percent), and primary hepatic metabolism through CYP3A4 with secondary contributions from CYP2C19, CYP1A2, CYP2C9, and CYP2D6 [5]. In vivo metabolite identification studies in rats, horses, and humans have collectively characterized 21 or more phase I and phase II metabolites, predominantly monohydroxylated and bishydroxylated species formed on the azabicyclic ring system, along with glucuronide conjugates [6, 7, 8]. Predicted plasma half-life is approximately 1.18 hours, though this value derives from computational models and has not been confirmed in formal human pharmacokinetic studies [5].

ACP-105 has never entered human clinical trials. No Phase 1, Phase 2, or Phase 3 studies are registered or reported. The compound was nominated as a development candidate by ACADIA Pharmaceuticals in February 2006 for potential treatment of muscle wasting and osteoporosis, and preclinical data were presented at the Experimental Biology 2008 meeting, but development was subsequently discontinued. The compound is classified as a prohibited substance under World Anti-Doping Agency (WADA) regulations since 2008, and adverse analytical findings for ACP-105 have appeared in routine sports doping control samples [6, 9]. Research-grade ACP-105 is available from multiple chemical suppliers at greater than 98 percent purity. This monograph reviews the chemistry, structure-activity relationships, and characterization of ACP-105; the androgen receptor partial agonist mechanism and tissue selectivity; the available absorption, distribution, metabolism, and excretion data; the preclinical pharmacology in musculoskeletal and central nervous system models; the absence of clinical evidence; sourcing and quality verification; reconstitution and handling; stack interaction considerations; adverse event and safety signals; and a comparative assessment of five alternative SARM compounds against ACP-105 on five competency standards.

Ligandrol (LGD-4033, VK5211; CAS 1165910-22-4; molecular formula C14H12F6N2O; molecular weight 338.25) is a non-steroidal SARM developed by Ligand Pharmaceuticals (later out-licensed to Viking Therapeutics as VK5211). The compound is a high-affinity AR ligand (Ki approximately 1 nM, several-fold higher affinity than ostarine) with tissue-selective agonism similar to other SARMs. Phase 1 trials in healthy male volunteers demonstrated dose-dependent increases in lean body mass at doses of 0.1 to 1 mg daily over 21 days, with no significant prostate effects but with HPG axis suppression at the higher dose tier. Subsequent phase 2 development (VK5211) targeted hip fracture recovery; results have been intermittent. Plasma half-life is approximately 24 to 36 hours. The compound is widely used recreationally at supratherapeutic doses (5 to 10 mg) and is banned by WADA. Used as the canonical high-affinity SARM in mechanism studies.

S-23 (CAS 1010396-29-8; molecular formula C18H13ClF4N2O3; molecular weight 416.76) is a non-steroidal SARM developed by GTx. Distinct among SARMs as a full AR agonist (rather than a partial agonist), producing more pronounced HPG axis suppression alongside strong anabolic activity. Preclinical studies in male rodents demonstrated reversible spermatogenesis suppression; the compound was investigated as a candidate for male hormonal contraception via combined progestin and SARM regimen. Tissue-selective effects: full agonism in muscle and bone with reduced prostate activity relative to testosterone. The strong HPG suppression makes S-23 the most stringent SARM in terms of post-cycle endocrine recovery. No human clinical trials at this writing. Used recreationally despite the suppressive profile.

LGD-3303 (9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one; molecular formula C16H14ClF3N2O; molecular weight 342.74) is a non-steroidal SARM developed by Ligand Pharmaceuticals as a candidate for osteoporosis. Preclinical studies in ovariectomized rats demonstrated strong bone anabolic activity comparable to or exceeding raloxifene at appropriate doses, with reduced prostate effects. Tissue selectivity profile favors bone over muscle within the SARM class. Phase 1 human studies were conducted but the compound did not advance to phase 2. The compound retains research utility for bone-focused SARM pharmacology and is occasionally used recreationally. Plasma half-life is approximately 24 hours.