2. Academic Validation
  3. 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

  • J Med Chem. 2019 Nov 14;62(21):9874-9889. doi: 10.1021/acs.jmedchem.9b01283.
Alison D Findlay 1,  Jonathan S Foot 1,  Alberto Buson 1,  Mandar Deodhar 1,  Andrew G Jarnicki 2,  Philip M Hansbro 2 3 4,  Gang Liu 3 4,  Heidi Schilter 1,  Craig I Turner 1,  Wenbin Zhou 1,  Wolfgang Jarolimek 1
Affiliations

Affiliations

  • 1 Pharmaxis Ltd , 20 Rodborough Road, Frenchs Forest , Sydney , New South Wales 2086 , Australia.
  • 2 Centre for Healthy Lungs , The University of Newcastle and Hunter Medical Research Institute , Newcastle , New South Wales 2300 , Australia.
  • 3 Centre for Inflammation , Centenary Institute , Sydney , New South Wales 2050 , Australia.
  • 4 Faculty of Science , University of Technology Sydney , Ultimo , New South Wales 2007 , Australia.
PMID: 31580073 DOI: 10.1021/acs.jmedchem.9b01283
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.

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