title: An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate.
abstract: A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids, suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.
authors.affiliation: Research Development, Ligand Pharmaceuticals Inc., San Deigo, California 92121, USA. jminer@ligand.com
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
authors.forename: William
authors.initials: W
authors.lastname: Chang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Chapman
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Finn
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Hong
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López
authors.forename: Keith B
authors.initials: KB
authors.lastname: Marschke
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
authors.forename: William
authors.initials: W
authors.lastname: Schrader
authors.forename: Russell
authors.initials: R
authors.lastname: Turner
authors.forename: Arjan
authors.initials: A
authors.lastname: van Oeveren
authors.forename: Humberto
authors.initials: H
authors.lastname: Viveros
authors.forename: Lin
authors.initials: L
authors.lastname: Zhi
authors.forename: Andres
authors.initials: A
authors.lastname: Negro-Vilar
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D003307:Copulation / Q000187:drug effects*; D005474:Fluoxymesterone / Q000494:pharmacology; D006801:Humans; D008159:Lumbar Vertebrae / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects*; D009919:Orchiectomy; D012516:Osteosarcoma; D011467:Prostate / Q000187:drug effects*; D011471:Prostatic Neoplasms; D015363:Quinolones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D018411:Spodoptera
chemical_list: C515129:6-N,N-bis(2,2,2-trifluoroethyl)amino-4-trifluoromethylquinolin-2(1H)-one; D000634:Aminoquinolines; D018931:Antineoplastic Agents, Hormonal; D015363:Quinolones; D011944:Receptors, Androgen; D005474:Fluoxymesterone