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

doi:10.1021/acs.jmedchem.7b00271

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 journal › Article › peer-review

29 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 K_i = 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 language	English (US)
Pages (from-to)	3979-4001
Number of pages	23
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00271
State	Published - May 11 2017

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair",

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.",

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AU - Antczak, Monika I.

AU - Zhang, Yongyou

AU - Wang, Changguang

AU - Doran, Jennifer

AU - Naidoo, Jacinth

AU - Voruganti, Sukesh

AU - Williams, Noelle S.

AU - Markowitz, Sanford D.

AU - Ready, Joseph M.

PY - 2017/5/11

Y1 - 2017/5/11

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AB - 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.

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Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair

Abstract

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