Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs)
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- 作者：Anthony L. Handlon ; Lee T. Schaller ; Lisa M. Leesnitzer ; Raymond V. Merrihew ; Chuck Poole ; John C. Ulrich ; Joseph W. Wilson ; Rodolfo Cadilla ; Philip Turnbull
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：January 14, 2016
- 年：2016
- 卷：7
- 期：1
- 页码：83-88
- 全文大小：465K
- ISSN：1948-5875
文摘
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%).