Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption

  • J Med Chem. 2005 Apr 21;48(8):2957-63. doi: 10.1021/jm040209d.
John M Sanders  1 ,  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
Affiliations
  • 1. Department of Chemistry, 600 South Mathews Avenue, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
PMID: 15828834 DOI: 10.1021/jm040209d
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.