TY - JOUR
T1 - Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair
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.
N1 - Funding Information:
Financial support is from the NIH (Grants R01 GM102403, R01 CA216863, J.M.R.), the Welch Foundation (Grant I-1612, J.M.R.), and CPRIT (Grant RP110708-C3, N.S.W.). The Preclinical Pharmacology Core (N.S.W.) is supported in part by funding from the Institute for Innovations in Medicine at UTSW. Additional funding is from the NIH (Grant P50 CA150964, S.D.M.) and a Scholar Innovator Award from the Harrington Discovery Institute (S.D.M.).
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/5/11
Y1 - 2017/5/11
N2 - 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.
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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U2 - 10.1021/acs.jmedchem.7b00271
DO - 10.1021/acs.jmedchem.7b00271
M3 - Article
C2 - 28398755
AN - SCOPUS:85019197794
SN - 0022-2623
VL - 60
SP - 3979
EP - 4001
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -