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Received for publication June 27, 2002.
Revised August 2, 2002.
Accepted for publication December 9, 2002.
The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacologic 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 Ki 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 pharmacologic activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, while levator ani muscle weight was used as a measure of anabolic activity. The maximal response (Emax) and dose for half-maximal effect (ED50) were determined for each compound and compared to 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 LH or FSH suppression at doses near the ED50. 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.
Key words:
androgen, hormone, muscle, pharmacology, receptor, testosterone
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