Synthesis of potent and tissue-selective androgen receptor modulators (SARMs): 2-(2,2,2)-Trifluoroethyl-benzimidazole scaffold

Raymond A Ng; James C Lanter; Vernon C Alford; George F Allan; Tifanie Sbriscia; Scott G Lundeen; Zhihua Sui

doi:10.1016/j.bmcl.2006.12.045

Synthesis of potent and tissue-selective androgen receptor modulators (SARMs): 2-(2,2,2)-Trifluoroethyl-benzimidazole scaffold

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1784-7. doi: 10.1016/j.bmcl.2006.12.045. Epub 2006 Dec 21.

Authors

Raymond A Ng¹, James C Lanter, Vernon C Alford, George F Allan, Tifanie Sbriscia, Scott G Lundeen, Zhihua Sui

Affiliation

¹ Johnson & Johnson Pharmaceutical Research and Development, LLC, Drug Discovery, 665 Stockton Drive, Exton, PA 19341, USA.

PMID: 17197181
DOI: 10.1016/j.bmcl.2006.12.045

Abstract

The synthesis and in vivo SAR of 2-(2,2,2)-trifluoroethyl-benzimidazoles are described. Prostate antagonism and/or levator ani agonism can be modulated by varying the substitution at the 2-position of 5,6-dichloro-benzimidazoles. Potent androgen agonists on the muscle were discovered that strongly bind to the androgen receptor (2-17 nM) and show potent in vivo efficacy (0.03-0.11 mg/day). True SARMs showing both prostate antagonism and levator ani agonism were revealed.

MeSH terms

Androgen Receptor Antagonists
Androgens
Animals
Benzimidazoles / agonists
Benzimidazoles / antagonists & inhibitors
Benzimidazoles / chemical synthesis*
Dose-Response Relationship, Drug
Indicators and Reagents
Male
Models, Molecular
Muscle, Smooth / drug effects
Muscle, Smooth / metabolism
Organ Size / drug effects
Prostate / drug effects
Prostate / metabolism
Rats
Rats, Sprague-Dawley
Receptors, Androgen / drug effects*
Structure-Activity Relationship

Substances

2-(2,2,2)-trifluoroethyl-benzimidazole
Androgen Receptor Antagonists
Androgens
Benzimidazoles
Indicators and Reagents
Receptors, Androgen