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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.

SUBMITTER: Antczak MI

PROVIDER: S-EPMC5580352 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair.

Antczak Monika I MI Zhang Yongyou Y Wang Changguang C Doran Jennifer J Naidoo Jacinth J Voruganti Sukesh S Williams Noelle S NS Markowitz Sanford D SD Ready Joseph M JM

Journal of medicinal chemistry 20170425 9

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<sub>i</sub> = 0.1 nM in vitro, doubles PGE2 levels in vivo, and shows efficacy in mouse models of re ...[more]

PMID: 28398755

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Structural Insights into Novel 15-Prostaglandin Dehydrogenase Inhibitors.

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