- Title
- Identification and optimization of mechanism-based fluoroallylamine inhibitors of lysyl oxidase-like 2/3
- Creator
- Findlay, Alison D.; Foot, Jonathan S.; Buson, Alberto; Deodhar, Mandar; Jarnicki, Andrew G.; Hansbro, Philip M.; Liu, Gang; Schilter, Heidi; Turner, Craig I.; Zhou, Wenbin; Jarolimek, Wolfgang
- Relation
- NHMRC.1079187 http://purl.org/au-research/grants/nhmrc/1079187
- Relation
- Journal of Medicinal Chemistry Vol. 62, Issue 21, p. 9874-9889
- Publisher Link
- http://dx.doi.org/10.1021/acs.jmedchem.9b01283
- Publisher
- American Chemical Society
- Resource Type
- journal article
- Date
- 2019
- Description
- 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.
- Subject
- enzyme; lung fibrosis; liver fibrosis; anti-fibrotic activity
- Identifier
- http://hdl.handle.net/1959.13/1443106
- Identifier
- uon:41886
- Identifier
- ISSN:0022-2623
- Language
- eng
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