title: Pharmacodynamics of selective androgen receptor modulators.
abstract: The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Wenqing
authors.initials: W
authors.lastname: Gao
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearbey
authors.forename: Huiping
authors.initials: H
authors.lastname: Xu
authors.forename: Kiwon
authors.initials: K
authors.lastname: Chung
authors.forename: Yali
authors.initials: Y
authors.lastname: He
authors.forename: Craig A
authors.initials: CA
authors.lastname: Marhefka
authors.forename: Karen A
authors.initials: KA
authors.lastname: Veverka
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D000813:Anilides; D012739:Gonadal Steroid Hormones; C473215:N-phenyl-3-(4-acetamidophenoxy)-2-hydroxy-2-methylpropanamide; C473214:N-phenyl-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropanamide; D011944:Receptors, Androgen; D013739:Testosterone