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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1021/acs.jmedchem.9b01283
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 62
Number: 21
Page Range: pp. 9874-9889
Date: 2019
Divisions: UTS Centre for Inflammation
Depositing User: General Admin
Identification Number: 10.1021/acs.jmedchem.9b01283
ISSN: 0022-2623
Date Deposited: 21 Dec 2020 23:27
Abstract:

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.

Creators:
Creators
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Findlay, Alison D.
UNSPECIFIED
Foot, Jonathan S.
UNSPECIFIED
Buson, Alberto
UNSPECIFIED
Deodhar, Mandar
UNSPECIFIED
Jarnicki, Andrew G.
UNSPECIFIED
Hansbro, Philip M.
UNSPECIFIED
Liu, Gang
UNSPECIFIED
Schilter, Heidi
UNSPECIFIED
Turner, Craig I.
UNSPECIFIED
Zhou, Wenbin
UNSPECIFIED
Jarolimek, Wolfgang
UNSPECIFIED
Last Modified: 21 Dec 2020 23:27
URI: https://eprints.centenary.org.au/id/eprint/134

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