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This version published online on September 15, 2005
Endocrinology, doi:10.1210/en.2005-0732
A more recent version of this article appeared on December 1, 2005
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Submitted on June 16, 2005
Accepted on September 6, 2005

In Vitro and In Vivo Structure-Activity Relationships of Novel Androgen Receptor Ligands with Multiple Substituents in the B-Ring

Jiyun Chen, Dong Jin Hwang, Kiwon Chung, Casey E. Bohl, Scott J. Fisher, Duane D. Miller, and James T. Dalton*

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163

* To whom correspondence should be addressed. E-mail: DALTON.1{at}OSU.EDU.

We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissue-selective pharmacologic activity, identifying these S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides analogs as the first members of a new class of drugs known as selective androgen receptor modulators (SARMs). The purpose of these studies was to explore additional structure-activity relationships (SAR) of SARMs to enhance their AR binding affinity, AR-mediated transcriptional activation, and in vivo pharmacologic activity. The AR binding affinity (Ki) of 29 novel synthetic AR ligands was determined by a radioligand competitive binding assay and ranged from 1.0 to 51 nM. Compounds with electron-withdrawing substituents at the para- and meta-positions of the B-ring demonstrated the highest AR binding affinity. The AR-mediated transcriptional activation was determined using a co-transfection assay in CV-1 cells. Most compounds with two substituents in the B-ring maintained or improved their functional activity in vitro. However, compounds with three halogen substituents exhibited significant regioselectivity. Fifteen compounds were selected to examine their pharmacologic activity in castrated rats. In vivo pharmacologic activity and selectivity were significantly changed by structural modification in the B-ring. Compounds with halogen groups at the para- and meta-positions of the B-ring displayed the highest pharmacologic activity. Incorporating substituents at the ortho-position of the B-ring resulted in poor pharmacologic activity. In vitro and in vivo agonist activity were partially correlated. In conclusion, novel SARMs with improved in vivo pharmacologic activity can be designed and synthesized based on the SAR identified in these studies.
Key words: Structural-activity relationship (SAR) • AR • SARM




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