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

6 Citations (Scopus)

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

Fingerprint

Prostaglandin Antagonists
Dinoprostone
Prostaglandins
Oxidoreductases
Regeneration
Hepatectomy
Bone Marrow Transplantation
Ulcerative Colitis
Solubility
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. / Antczak, Monika I.; Zhang, Yongyou; Wang, Changguang; Doran, Jennifer; Naidoo, Jacinth; Voruganti, Sukesh; Williams, Noelle S.; Markowitz, Sanford D.; Ready, Joseph M.

In: Journal of Medicinal Chemistry, Vol. 60, No. 9, 11.05.2017, p. 3979-4001.

Research output: Contribution to journalArticle

Antczak, MI, Zhang, Y, Wang, C, Doran, J, Naidoo, J, Voruganti, S, Williams, NS, Markowitz, SD & Ready, JM 2017, 'Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair', Journal of Medicinal Chemistry, vol. 60, no. 9, pp. 3979-4001. https://doi.org/10.1021/acs.jmedchem.7b00271
Antczak MI, Zhang Y, Wang C, Doran J, Naidoo J, Voruganti S et al. Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. Journal of Medicinal Chemistry. 2017 May 11;60(9):3979-4001. https://doi.org/10.1021/acs.jmedchem.7b00271
Antczak, Monika I. ; Zhang, Yongyou ; Wang, Changguang ; Doran, Jennifer ; Naidoo, Jacinth ; Voruganti, Sukesh ; Williams, Noelle S. ; Markowitz, Sanford D. ; Ready, Joseph M. / Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 9. pp. 3979-4001.
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