title: 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 μM), and high oral bioavailability in rats (83%).
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Handlon
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Lee T
authors.initials: LT
authors.lastname: Schaller
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leesnitzer
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Raymond V
authors.initials: RV
authors.lastname: Merrihew
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Chuck
authors.initials: C
authors.lastname: Poole
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Ulrich
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Wilson
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Cadilla
authors.affiliation: Metabolic Pathways Cardiovascular Unit and Platform Technology & Science, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States.
authors.forename: Philip
authors.initials: P
authors.lastname: Turnbull
keywords: LLE; SARM; androgen receptor; ligand efficiency; selective androgen receptor modulator
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