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Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs).

ABSTRACT: A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 ?M), and high oral bioavailability in rats (83%).

SUBMITTER: Handlon AL 

PROVIDER: S-EPMC4716610 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs).

Handlon Anthony L AL   Schaller Lee T LT   Leesnitzer Lisa M LM   Merrihew Raymond V RV   Poole Chuck C   Ulrich John C JC   Wilson Joseph W JW   Cadilla Rodolfo R   Turnbull Philip P  

ACS medicinal chemistry letters 20151119 1

A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700  ...[more]

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