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ACS Med Chem Lett. 2015 Nov 19;7(1):83-8. doi: 10.1021/acsmedchemlett.5b00377. eCollection 2016 Jan 14.

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

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Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.


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 μM), and high oral bioavailability in rats (83%).


LLE; SARM; androgen receptor; ligand efficiency; selective androgen receptor modulator

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