Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair

Monika I. Antczak, Yongyou Zhang, Changguang Wang, Jennifer Doran, Jacinth Naidoo, Sukesh Voruganti, Noelle S. Williams, Sanford D. Markowitz, Joseph M. Ready

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The enzyme 15-prostaglandin dehydrogenase (15-PGDH) catalyzes the first step in the degradation of prostaglandins including PGE2. It is a negative regulator of tissue repair and regeneration in multiple organs. Accordingly, inhibitors of 15-PGDH are anticipated to elevate in vivo levels of PGE2 and to promote healing and tissue regeneration. The small molecule SW033291 (1) inhibits 15-PGDH with Ki = 0.1 nM in vitro, doubles PGE2 levels in vivo, and shows efficacy in mouse models of recovery from bone marrow transplantation, ulcerative colitis, and partial hepatectomy. Here we describe optimized variants of 1 with improved solubility, druglike properties, and in vivo activity.

Original languageEnglish (US)
Pages (from-to)3979-4001
Number of pages23
JournalJournal of Medicinal Chemistry
Volume60
Issue number9
DOIs
StatePublished - May 11 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Antczak, M. I., Zhang, Y., Wang, C., Doran, J., Naidoo, J., Voruganti, S., Williams, N. S., Markowitz, S. D., & Ready, J. M. (2017). Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. Journal of Medicinal Chemistry, 60(9), 3979-4001. https://doi.org/10.1021/acs.jmedchem.7b00271