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. 2010 Dec 2;2(2):124-9.
doi: 10.1021/ml1002508. eCollection 2011 Feb 10.

Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140

Chris P Miller  1 , Maysoun Shomali  1 , C Richard Lyttle  1 , Louis St L O'Dea  1 , Hillary Herendeen  1 , Kyla Gallacher  1 , Dottie Paquin  1 , Dennis R Compton  2 , Bishwabhusan Sahoo  2 , Sean A Kerrigan  2 , Matthew S Burge  2 , Michael Nickels  2 , Jennifer L Green  2 , John A Katzenellenbogen  3 , Alexei Tchesnokov  4 , Gary Hattersley  1
Affiliations

Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140

Chris P Miller et al. ACS Med Chem Lett. .

Abstract

This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.

Keywords: Androgen; Herschberger assay; SARM; cachexia; oxadiazole; primate.

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Figures

Figure 1
Figure 1
Structures of testosterone (1), 5α-dihydrotestosterone (2), GTx S-22 (3), BMS 562929 (4), initial lead 5, active metabolite 6, and 7 (RAD140).
Scheme 1
Scheme 1. Synthesis of Compound 7 (RAD140)
Figure 2
Figure 2
Tissue-selective agonist activity of RAD140 in castrated immature rats. The muscle (levator ani) and prostate weights from animals treated for 11 days are plotted with sham and vehicle controls together with the SD. TP is testosterone propionate dosed subcutaneously daily in corn oil. Five rats were included in each treatment group. *p < 0.05 vs vehicle for prostate. §p < 0.05 vs vehicle for LABC.
Figure 3
Figure 3
Tissue-selective antagonist activity of RAD140. The muscle (levator ani), seminal vesicles, and prostate weights from castrated immature rats treated for 11 days are plotted as a percent of testosterone propionate (TP) together with the SD. *p < 0.05 vs TP for all tissues.
Figure 4
Figure 4
Tissue-selective agonist activity of RAD140 in young intact male rats. The muscle (levator ani) and prostate weights from intact immature rats treated for 11 days are plotted with sham and vehicle controls together with the SD. Eight rats were included in each treatment group. *p < 0.05 vs vehicle for prostate. §p < 0.05 vs vehicle for LABC.
Figure 5
Figure 5
Primate body weight from day −21, through 28 days dosing and 21 days postdosing with RAD140 (0.01, 0.1, and 1 mg/kg, po). Three monkeys were included for each treatment group. The change in baseline subtracted body weight from day −1 to day 29 was statistically significant for the 0.1 mg/kg (p < 0.01) and 1.0 mg/kg (p < 0.05) groups only. The change in body weight at day 29 between the 0.1 mg/kg group and the 0.01 mg/kg group was statistically significant (p < 0.05) but not for 1.0 mg/kg and the 0.01 mg/kg group (p < 0.1).
Figure 6
Figure 6
Mean change in primate tissue weight as measured by DEXA analysis at day −2 and day 29. Standard deviation for fat (36, 36, 40) and lean tissue (65, 205, 188) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively. None of the changes were statistically significant (p > 0.05).
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