Design and synthesis of bisphosphonate analogs as inhibitors of farnesyl pyrophosphate synthase.

摘要

Molecular modeling and synthetic studies were carried out on several novel analogs of risedronate, a nitrogen-containing bisphosphonate (N-BP) drug that is widely used for the treatment of osteoporosis and other bone diseases. The physicochemical properties of the side-chain nitrogen and its position relative to the bisphosphonate P-C-P backbone are associated with the potency of N-BPs in inhibiting human farnesyl pyrophosphate synthase (FPPS), which is believed to be the biochemical target of these drugs. By computer-simulated docking with AutoDock 3 and predictive pKa calculation studies, we designed a small library of compounds to examine the relationship between nitrogen basicity and drug potency in risedronate analogs. A number of analogs, containing either electron-donating or electronwithdrawing substituents on the pyridinyl ring system, were evaluated for antiresorptive potency in a standard assay.;The docking software was further used to evaluate a series of risedronate analogs in which alkyl substituents of variable length replaced the alpha-OH group attached to the carbon atom of the P-C-P bisphosphonate backbone. Representative examples were synthesized and submitted for evaluation of anti-resorptive activity, as well as for Xray crystallographic analysis of the FPPS-inhibitor complexes.;Inhibitor-active site docking analysis, synthesis, and X-ray crystallography of the inhibitor-enzyme complex were also applied to the interactions of FPPS with [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid), NE-10501, an analog of risedronate in which the side-chain configuration is rigidified by incorporation of a fused 5-membered ring. A docking analysis predicted preferential binding of the R-enantiomer. To test this prediction, the compound was resynthesized using a significantly improved synthetic method developed in our laboratory. X-ray crystallographic analysis of the inhibitor-enzyme complex confirmed the presence of only the R-enantiomer in the active site. However, the Xray data indicated that the Mg2+ ion content of the active site was lower than in the risedronate complex, suggesting an explanation for the relatively decreased potency of NE-10501 as compared to the clinically employed drug.;Preliminarily to the above investigations, detailed synthetic procedures were worked out for the following benchmark N-BP compounds: [1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid), (hydroxymethylene)bis(phosphonic acid), and [2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid). Several unsuccessful attempts to synthesize the first example of a tetrakisphosphonate also are outlined.