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

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Patnaik A, Axford L, Deng L, Cohick E, Ren X, Loi S, Kecman S, Hollis-Symynkywicz M, Harrison TJ, Papillon JPN, Dales N, Hamann LG, Lee L, Regard JB, Marcinkeviciene J, Marro ML, Patterson AW

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

Bioorg Med Chem. 2020 Jun 15;28(12):115548. doi: 10.1016/j.bmc.2020.115548. Epub 2020 May 12.

PubMed ID

32503688 [ View in PubMed

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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.