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

Findlay, AD; Foot, JS; Buson, A; Deodhar, M; Jarnicki, AG; Hansbro, PM; Liu, G; Schilter, H; Turner, CI; Zhou, W; Jarolimek, W

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

Findlay, AD Foot, JS

Buson, A Deodhar, M Jarnicki, AG Hansbro, PM

Liu, G

Schilter, H Turner, CI Zhou, W Jarolimek, W

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Publication Type:: Journal Article
Citation:: Journal of Medicinal Chemistry, 2019, 62 (21), pp. 9874 - 9889
Issue Date:: 2019-11-14

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Field	Value	Language
dc.contributor.author	Findlay, AD	en_US
dc.contributor.author	Foot, JS https://orcid.org/0000-0003-1642-1742	en_US
dc.contributor.author	Buson, A	en_US
dc.contributor.author	Deodhar, M	en_US
dc.contributor.author	Jarnicki, AG	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638	en_US
dc.contributor.author	Schilter, H	en_US
dc.contributor.author	Turner, CI	en_US
dc.contributor.author	Zhou, W	en_US
dc.contributor.author	Jarolimek, W	en_US
dc.date.issued	2019-11-14	en_US
dc.identifier.citation	Journal of Medicinal Chemistry, 2019, 62 (21), pp. 9874 - 9889	en_US
dc.identifier.issn	0022-2623	en_US
dc.identifier.uri	http://hdl.handle.net/10453/136757
dc.description.abstract	Copyright © 2019 American Chemical Society. 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.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1079187
dc.relation.ispartof	Journal of Medicinal Chemistry	en_US
dc.relation.isbasedon	10.1021/acs.jmedchem.9b01283	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.title	Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3	en_US
dc.type	Journal Article
utslib.citation.volume	21	en_US
utslib.citation.volume	62	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	21	en_US
pubs.publication-status	Published	en_US
pubs.volume	62	en_US

Abstract:

Copyright © 2019 American Chemical Society. 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/136756