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

D L Soper; J B Milbank; G E Mieling; M J Dirr; A S Kende; R Cooper; W S Jee; W Yao; J L Chen; M Bodman; M W Lundy; B De; M E Stella; F H Ebetino; Y Wang; M A deLong; J A Wos

doi:10.1021/jm010264b

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

J Med Chem. 2001 Nov 22;44(24):4157-69. doi: 10.1021/jm010264b.

Authors

D L Soper¹, J B Milbank, G E Mieling, M J Dirr, A S Kende, R Cooper, W S Jee, W Yao, J L Chen, M Bodman, M W Lundy, B De, M E Stella, F H Ebetino, Y Wang, M A deLong, J A Wos

Affiliation

¹ Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.

PMID: 11708917
DOI: 10.1021/jm010264b

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.

MeSH terms

Absorptiometry, Photon
Amino Acid Sequence
Animals
Binding, Competitive
Bone Density / drug effects
Bone and Bones / diagnostic imaging
Bone and Bones / drug effects*
Bone and Bones / metabolism
COS Cells
Dinoprost / analogs & derivatives
Dinoprost / chemical synthesis*
Dinoprost / chemistry
Dinoprost / metabolism
Dinoprost / pharmacology
Female
Humans
Models, Molecular
Molecular Sequence Data
Osteoporosis / drug therapy
Ovariectomy
Phosphinic Acids / chemical synthesis*
Phosphinic Acids / chemistry
Phosphinic Acids / metabolism
Phosphinic Acids / pharmacology
Prostaglandins F, Synthetic / chemical synthesis*
Prostaglandins F, Synthetic / chemistry
Prostaglandins F, Synthetic / metabolism
Prostaglandins F, Synthetic / pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Prostaglandin / metabolism
Structure-Activity Relationship
Tomography, X-Ray Computed
Transfection

Substances

2-decarboxy-2-(P-methylphosphinico)-16-phenoxytetranorprostaglandin F(2alpha)
Phosphinic Acids
Prostaglandins F, Synthetic
Receptors, Prostaglandin
Dinoprost