Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3
| Autor: | Wolfgang Jarolimek, Andrew G. Jarnicki, Heidi Schilter, Jonathan Stuart Foot, Philip M. Hansbro, Craig Ivan Turner, Zhou Wenbin, Mandar Deodhar, Gang Liu, Alison D. Findlay, Alberto Buson |
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| Rok vydání: | 2019 |
| Předmět: |
Amine oxidase
Lysyl oxidase 01 natural sciences Extracellular matrix Protein-Lysine 6-Oxidase 03 medical and health sciences Mice Drug Discovery Animals Humans Amines Enzyme Inhibitors 030304 developmental biology chemistry.chemical_classification Indole test 0303 health sciences LOXL3 LOXL2 biology Chemistry Triazoles 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Biochemistry Drug Design biology.protein Molecular Medicine Elastin |
| Zdroj: | Journal of medicinal chemistry. 62(21) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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