- Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.
Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.
Journal of medicinal chemistry (2005-04-15)
John M Sanders, Yongcheng Song, Julian M W Chan, Yonghui Zhang, Samuel Jennings, Thomas Kosztowski, Sarah Odeh, Ryan Flessner, Christine Schwerdtfeger, Evangelia Kotsikorou, Gary A Meints, Aurora Ortiz Gómez, Dolores González-Pacanowska, Amy M Raker, Hong Wang, Ermond R van Beek, Socrates E Papapoulos, Craig T Morita, Eric Oldfield
PMID15828834
ABSTRACT
We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.
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