Discovery of 1-((6-Aminopyridin-3-yl)Methyl)-3-(4-Bromophenyl)Urea as a Potent, Irreversible Myeloperoxidase Inhibitor

  • J Pharmacol Exp Ther. 2018 Oct;367(1):147-154. doi: 10.1124/jpet.118.248435.
Martin L Marro  1 ,  Andrew W Patterson  1 ,  Lac Lee  1 ,  Lin Deng  1 ,  Aimee Reynolds  1 ,  Xianglin Ren  1 ,  Laura Axford  1 ,  Anup Patnaik  1 ,  Micah Hollis-Symynkywicz  1 ,  Nigel Casson  1 ,  Dominique Custeau  1 ,  Lisa Ames  1 ,  Sally Loi  1 ,  Lihe Zhang  1 ,  Toshiyuki Honda  1 ,  Jutta Blank  1 ,  Tyler J Harrison  1 ,  Julien P N Papillon  1 ,  Lawrence G Hamann  1 ,  Jovita Marcinkeviciene  1 ,  Jean B Regard  2
Affiliations
  • 1. Cardiovascular and Metabolic Diseases (M.L.M., L.L., X.R., L.Ax., M.H.-S., N.C., D.C., L.Am., S.L., L.Z., T.H., J.M., J.B.R.), Global Discovery Chemistry (A.W.P., A.P., T.J.H., J.P.N.P., L.G.H.), PK Sciences (L.D.), Technical R&D (A.R.), and Chemical Biology and Therapeutics (J.B.), Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • 2. Cardiovascular and Metabolic Diseases (M.L.M., L.L., X.R., L.Ax., M.H.-S., N.C., D.C., L.Am., S.L., L.Z., T.H., J.M., J.B.R.), Global Discovery Chemistry (A.W.P., A.P., T.J.H., J.P.N.P., L.G.H.), PK Sciences (L.D.), Technical R&D (A.R.), and Chemical Biology and Therapeutics (J.B.), Novartis Institutes for BioMedical Research, Cambridge, Massachusetts [email protected].
PMID: 30076263 DOI: 10.1124/jpet.118.248435
Abstract

Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including Cardiovascular Disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of Peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease.

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