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.
Anup Patnaik  1 ,  Laura Axford  2 ,  Lin Deng  3 ,  Evan Cohick  2 ,  Xianglin Ren  2 ,  Sally Loi  2 ,  Sam Kecman  2 ,  Micah Hollis-Symynkywicz  2 ,  Tyler J Harrison  4 ,  Julien P N Papillon  4 ,  Natalie Dales  4 ,  Lawrence G Hamann  4 ,  Lac Lee  2 ,  Jean B Regard  2 ,  Jovita Marcinkeviciene  2 ,  Martin L Marro  2 ,  Andrew W Patterson  5
Affiliations
  • 1. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States. Electronic address: [email protected].
  • 2. Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States.
  • 3. PK Sciences, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States.
  • 4. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States.
  • 5. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States. Electronic address: [email protected].
PMID: 32503688 DOI: 10.1016/j.bmc.2020.115548
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.

Keywords
Indole; Irreversible inhibitor; MPO; Mechanism-based inhibitor; Myeloperoxidase; Peroxidase; TPO.
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