Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs)

被引：23

作者：

Handlon, Anthony L. ^{[1
]}

Schaller, Lee T.

Leesnitzer, Lisa M. ^{[2
]}

Merrihew, Raymond V.

Poole, Chuck

Ulrich, John C.

Wilson, Joseph W.

Cadilla, Rodolfo

Turnbull, Philip ^{[3
]}

机构：

[1] GlaxoSmithKline, Metab Pathways Cardiovasc Unit, 709 Swedeland Rd, King Of Prussia, PA 19406 USA

[2] Quintiles, Plaza Bldg,4820 Emperor Blvd, Durham, NC 27703 USA

[3] Receptos Inc, 3033 Sci Pk Rd,Suite 300, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 01期

关键词：

ligand efficiency; LLE; androgen receptor; selective androgen receptor modulator; SARM; DRUG DISCOVERY; MEN; METRICS; IMPACT; WOMEN; ACID;

D O I：

10.1021/acsmedchemlett.5b00377

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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

引用

页码：83 / 88

页数：6

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