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Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO)

Patnaik, Anup and Axford, Laura and Deng, Lin and Ren, Xianglin and Kecman, Sam and Hollis-Symynkywicz, Micah and Harrison, Tyler and Papillon, Julien and Dales, Natalie and Lee, Lac and Regard, Jean and Marcinkeviciene, Jovita and Marro, Martin and Patterson, Andrew (2020) Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO). Bioorganic and Medicinal Chemistry, 28 (12). ISSN 14643391

Abstract

Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. Herein, we describe the development of a novel biaryl, indole-pyrazole series of irreversible mechanism-based inhibitors of MPO. Derived from an indole-containing high-throughput screen hit, optimization efforts resulted in potent and selective 6-substituted indoles with good oral bioavailability and in vivo activity.

Item Type: Article
Keywords: Indole Irreversible inhibitor Mechanism-based inhibitor MPO Myeloperoxidase Peroxidase TPO
Date Deposited: 30 Jul 2020 00:45
Last Modified: 30 Jul 2020 00:45
URI: https://oak.novartis.com/id/eprint/42686

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