Document Report Card

ID: ALA1134785

Journal: J Med Chem

Title: Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.

Authors: Soper DL, Milbank JB, Mieling GE, Dirr MJ, Kende AS, Cooper R, Jee WS, Yao W, Chen JL, Bodman M, Lundy MW, De B, Stella ME, Ebetino FH, Wang Y, deLong MA, Wos JA.

Abstract: A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

CiteXplore: 11708917

DOI: 10.1021/jm010264b