Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 9, Pages 3979-4001Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00271
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Funding
- NIH [R01 GM102403, R01 CA216863, P50 CA150964]
- Welch Foundation [I-1612]
- CPRIT [RP110708-C3]
- Institute for Innovations in Medicine at UTSW
- Harrington Discovery Institute
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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.
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