ACP-105 is a tricyclic SARM from Acadia Pharmaceuticals that binds the androgen receptor with high affinity and shows the typical SARM profile of muscle and bone effects with reduced prostate activity in castrated rat models. Acadia briefly explored cognitive applications based on androgen receptor expression in the prefrontal cortex and hippocampus, but development never reached human trials. There are no published pharmacokinetic data in people. It is sold as a research chemical primarily on the strength of its name appearing in old patent literature. The evidence base is thin even by SARM standards. 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 Kodiac editorial, not peer-reviewed.
Nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity and tissue-selective anabolic profile
A chlorinated aryl nitrile selective androgen receptor modulator discovered at ACADIA Pharmaceuticals through receptor selection and amplification technology screening, distinguished by partial agonist activity at the androgen receptor, tissue-selective anabolic effects on muscle and bone with minimal prostatic stimulation, and preclinical neuroprotective activity in irradiation and Alzheimer’s disease models.
Abstract
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.
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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.