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
收藏
页码：83 / 88
页数：6
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