Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3

被引：46

作者：

Findlay, Alison D. ^{[1
]}

Foot, Jonathan S. ^{[1
]}

Buson, Alberto ^{[1
]}

Deodhar, Mandar ^{[1
]}

Jarnicki, Andrew G. ^{[2
,3
,6
]}

Hansbro, Philip M. ^{[2
,3
,4
,5
]}

Liu, Gang ^{[4
,5
]}

Schilter, Heidi ^{[1
]}

Turner, Craig I. ^{[1
]}

Zhou, Wenbin ^{[1
]}

Jarolimek, Wolfgang ^{[1
]}

机构：

[1] Pharmaxis Ltd, 20 Rodborough Rd, Sydney, NSW 2086, Australia

[2] Univ Newcastle, Ctr Hlth Lungs, Newcastle, NSW 2300, Australia

[3] Hunter Med Res Inst, Newcastle, NSW 2300, Australia

[4] Centenary Inst, Ctr Inflammat, Sydney, NSW 2050, Australia

[5] Univ Technol Sydney, Fac Sci, Ultimo, NSW 2007, Australia

[6] Univ Melbourne, Dept Pharmacol & Therapeut, Parkville, Vic 3010, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 21期

基金：

英国医学研究理事会;

关键词：

IDIOPATHIC PULMONARY-FIBROSIS; SENSITIVE AMINE OXIDASES; MONOAMINE-OXIDASE; LIVER FIBROSIS; COLLAGEN; LUNG; PURIFICATION; SIMTUZUMAB; EXPRESSION; IMATINIB;

D O I：

10.1021/acs.jmedchem.9b01283

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-links in extracellular matrix proteins, namely, collagen and elastin, and is indicated in fibrotic diseases. Herein, we report the identification and subsequent optimization of a series of indole-based fluoroallylamine inhibitors of LOXL2. The result of this medicinal chemistry campaign is PXS-5120A (12k), a potent, irreversible inhibitor that is >300-fold selective for LOXL2 over LOX. PXS-5120A also shows potent inhibition of LOXL3, an emerging therapeutic target for lung fibrosis. Key to the development of this compound was the utilization of a compound oxidation assay. PXS-5120A was optimized to show negligible substrate activity in vitro for related amine oxidase family members, leading to metabolic stability. PXS-5120A, in a pro-drug form (PXS-5129A, 12o), displayed anti-fibrotic activity in models of liver and lung fibrosis, thus confirming LOXL2 as an important target in diseases where collagen cross-linking is implicated.

引用

页码：9874 / 9889

页数：16

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