Synthesis and Biological Evaluation of Prostaglandin-F Alkylphosphinic Acid Derivatives as Bone Anabolic Agents for the Treatment of Osteoporosis

• Published in: Journal of medicinal chemistry Vol. 44; no. 24; pp. 4157 - 4169
• Main Authors: Soper, David L, Milbank, Jared B. J, Mieling, Glen E, Dirr, Michelle J, Kende, Andrew S, Cooper, Robin, Jee, Webster S. S, Yao, Wei, Chen, Jian Liang, Bodman, Mark, Lundy, Mark W, De, Biswanath, Stella, Mark E, Ebetino, Frank H, Wang, Yili, deLong, Mitchell A, Wos, John A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.11.2001; Amer Chemical Soc
• Subjects: Absorptiometry, Photon; Amino Acid Sequence; Animals; Binding, Competitive; Biological and medical sciences; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Density - drug effects; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; COS Cells; Dinoprost - analogs & derivatives; Dinoprost - chemical synthesis; Dinoprost - chemistry; Dinoprost - metabolism; Dinoprost - pharmacology; Female; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Sequence Data; Osteoporosis - drug therapy; Ovariectomy; Pharmacology & Pharmacy; Pharmacology. Drug treatments; 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; Science & Technology; Structure-Activity Relationship; Tomography, X-Ray Computed; Transfection; F2-ALPHA ISOPROPYL ESTER; ANALOGS; PHOSPHOTYROSINE; RECEPTOR; F1-ALPHA; ANTIGLAUCOMA AGENTS; PHOSPHINATE ISOSTERES; OVARIECTOMIZED RATS; GRB2-SH2 DOMAIN INHIBITORS; STRUCTURE-BASED DESIGN; Human; Rat; Aliphatic compound; Rodentia; Selectivity; In vitro; Modeling; Phosphorus Organic compounds; Prevention; In vivo; Osteoporosis; Vertebrata; Biological fixation; Mammalia; Structure activity relation; Animal; Molecular model; Prostaglandin F; Affinity; Bone defect; Secondary alcohol; Chemical synthesis; Monocyclic compound; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010264b

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.