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.
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Monika I
authors.initials: MI
authors.lastname: Antczak
authors.affiliation: Department of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Yongyou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Changguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Doran
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Sukesh
authors.initials: S
authors.lastname: Voruganti
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.|Seidman Cancer Center, University Hospitals of Cleveland , Cleveland, Ohio 44106, United States.|Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Joseph M
authors.identifier: 0000-0003-1305-9581
authors.initials: JM
authors.lastname: Ready
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase