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

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.

An efficient synthesis of 3-hetero-13,14-dihydro prostaglandin F1alpha analogues.

[structure: see text]. A new class of 3-hetero-13,14-dihydro prostaglandin F(1)(alpha) analogues was synthesized from a common intermediate. The latter was constructed via a two-step, three-component process. The lower chain, containing the 15-(phenoxymethyl) group, was synthesized in enantiopure form using Jacobsen's (salen)Co-catalyzed kinetic resolution of a terminal epoxide with phenol.

The synthesis and human FP receptor binding affinity of 13,14-dihydro prostaglandin F1alpha sulfonamides: potential treatments for osteoporosis.

A novel class of saturated prostaglandin F2alpha sulfonamide analogs have been synthesized and evaluated in the human FP receptor binding assay for potential use in the treatment of osteoporosis. These compounds have been modified at the C1 carboxylic acid moiety and at the C16-C20 region of the prostaglandin. Based on the structure-activity relationships, it was found that at C1, the aryl sulfonamide analogs possessed greater affinity for the hFP receptor when compared to alkyl sulfonamides. When the sulfonamide was introduced into the C16-C20 region (omega chain) of the prostaglandin, a significant reduction in binding was observed. These results are discussed within the framework of a proposed model for the human FP receptor.

Synthesis and in vitro evaluation of human FP-receptor selective prostaglandin analogues.

The in vitro evaluation of a series of saturated prostaglandins revealed that compounds with omega chain aromatic rings retain nanomolar potency for the human prostaglandin F receptor (hFP receptor), exemplified by compound 8. In contrast, the double bonds are required for activity in the series with an acyclic omega chain as in PGF2alpha.

Design and synthesis of 13,14-dihydro prostaglandin F(1alpha) analogues as potent and selective ligands for the human FP receptor.

The in vitro evaluation of a new class of potential bone anabolic agents for the treatment of osteoporosis is described. These compounds are potent and selective ligands for the human prostaglandin F receptor (hFP receptor). The compounds lack the olefin unsaturation required for potency in the natural ligand PGF(2)(alpha) yet retain binding affinity for the hFP receptor in the nanomolar to micromolar range. Removal of the alkenes also results in a better selectivity ratio for the hFP receptor over the other prostaglandin receptors tested. A rationale for the selectivity differences of various analogues, based on ligand docking experiments to a putative hFP receptor model, is also described.