title: Synthesis and evaluation of water-soluble prodrugs of ursodeoxycholic acid (UDCA), an anti-apoptotic bile acid.
abstract: Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti-apoptotic activity in both in vitro and in vivo models. However, its utility is hampered by limited aqueous solubility. As such, water-soluble prodrugs of UDCA could have an advantage over the parent bile acid in indications where intravenous administration might be preferable, such as decreasing damage from stroke or acute kidney injury. Five phosphate prodrugs were synthesized, including one incorporating a novel phosphoryloxymethyl carboxylate (POMC) moiety. These prodrugs were highly water-soluble, but showed significant differences in chemical stability, with oxymethylphosphate prodrugs being the most unstable. In a series of NMR experiments, the POMC prodrug was bioactivated to UDCA by alkaline phosphatase (AP) faster than a prodrug containing a phosphate directly attached to the alcohol at the 3-position of UDCA. Both of these prodrugs showed significant anti-apoptotic activity in a series of in vitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP.
authors: Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA. pidosa@umn.edu
authors: Peter I
authors: PI
authors: Dosa
authors: Tim
authors: T
authors: Ward
authors: Rui E
authors: RE
authors: Castro
authors: Cecília M P
authors: CM
authors: Rodrigues
authors: Clifford J
authors: CJ
authors: Steer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects; D008297:Male; D008968:Molecular Conformation; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry*
chemical_list: D011355:Prodrugs; D053773:Transforming Growth Factor beta1; D014867:Water; D014580:Ursodeoxycholic Acid