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 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 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 (Emax) and dose for half-maximal effect (ED50) 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 ED50 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.
Footnotes
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The in vivo studies reported herein were supported by a grant from GTx, Inc. (Memphis, TN). In vitro pharmacological evaluation was supported by Grant R01 DK59800-01 from the National Institute of Diabetes and Digestive and Kidney Diseases (to J.T.D. and D.D.M.).
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DOI: 10.1124/jpet.102.040840
- Abbreviations:
- AR
- androgen receptor
- SARM
- selective androgen receptor modulator
- TP
- testosterone propionate
- PEG 300
- polyethylene glycol 300
- FSH
- follicle stimulating hormone
- LH
- luteinizing hormone
- ANOVA
- analysis of variance
- DHT
- dihydrotestosterone
- AST-SGOT
- serum glutamicoyaloacetic transominase
- ALT-SGPT
- serum glutamic pyruvic transaminase
- Received June 25, 2002.
- Accepted December 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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