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

D. L. Soper, J. B J Milbank, G. E. Mieling, M. J. Dirr, A. S. Kende, R. Cooper, W. S S Jee, Wei Yao, Liang Chen Jian Liang Chen, M. Bodman, M. W. Lundy, B. De, M. E. Stella, F. H. Ebetino, Y. Wang, M. A. Delong, J. A. Wos

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

A series of novel C1 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 C1 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 density (BMD) 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.

Original languageEnglish (US)
Pages (from-to)4157-4169
Number of pages13
JournalJournal of Medicinal Chemistry
Volume44
Issue number24
DOIs
StatePublished - Nov 22 2001
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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