P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K

被引：33

作者：

Barrett, DG

Boncek, VM

Catalano, JG

Deaton, DN ^{[1
]}

Hassell, AM

Jurgensen, CH

Long, ST

McFadyen, RB

Miller, AB

Miller, LR

Payne, JA

Ray, JA

Samano, V

Shewchuk, LM

Tavares, FX

Wells-Knecht, KJ

Willard, DH

Wright, LL

Zhou, HQQ

机构：

[1] GlaxoSmithKline, Dept Med Chem, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline, Dept Mol Pharmacol, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Discovery Res Computat Analyt & Struct Sci, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline, Dept World Wide Phys Properties, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline, Dept Res Bioanal & Drug Metab, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline, Dept Gene Express & Prot Purificat, Res Triangle Pk, NC 27709 USA

[7] GlaxoSmithKline, Discovery Res Biol, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 15期

关键词：

cathepsin K; cysteine protease inhibitors; ketoamide;

D O I：

10.1016/j.bmcl.2005.05.062

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the p(2)-p(3) linker and modifications to P-1' elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：3540 / 3546

页数：7

共 18 条

[1] Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1′, P1, and/or P3 substitutions [J].