| Autor: |
Findlay, AD, Foot, JS, Buson, A, Deodhar, M, Jarnicki, AG, Hansbro, PM, Liu, G, Schilter, H, Turner, CI, Zhou, W, Jarolimek, W |
| Rok vydání: |
2019 |
| Předmět: |
|
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
