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J Pharmacol Exp Ther. 2005 Oct;315(1):230-9. Epub 2005 Jun 29.

The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators.

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Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.


Selective androgen receptor modulators (SARMs) have many potential therapeutic applications, including male hypogonadism, osteoporosis, muscle-wasting diseases, sexual libido, and contraception. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides bearing a four-halogen substituent in the B-ring that displayed in vivo activity were identified in our previous study. Interestingly, in vivo pharmacological activity was not correlated with in vitro androgen receptor (AR) binding affinity. In this study, analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological activity. Studies also suggested that two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance) could be used to identify efficacious and potent SARMs. We tested this hypothesis using a series of four compounds incorporating either a nitro or cyano substituent at the para-position of the A- and B-aromatic rings. The S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-nitro-3-trifluromethylphenyl) propionamides (S-19 and S-20, respectively) and S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-cyano-3-trifluromethylphenyl) propionamides (S-21 and S-22, respectively) demonstrated high AR binding affinity, with Ki values ranging from 2.0 to 3.8 nM. Pharmacokinetic studies of selected compounds showed that the in vivo clearance of S-22 was the slowest followed sequentially by S-20, S-21, and S-19. The dose-response relationships for S-22 showed that S-22 exerted efficacious and selective activity in anabolic tissues at dose rates as low as 0.03 mg/day, indicative of the high potency of this compound in anabolic tissue (relative potency 4.41) and its potential for clinical use in androgen deficiency-related disorders.

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