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Alpha-halogenated analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC) were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e-h) and 3-PEHPC (7e-h) analogues had decreased bone mineral affinity, confirming that the alpha-OH group in 5 and 7 enhances bone affinity. The 5 alpha-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 (alpha-F) to 340 (alpha-Br) nM (5, 6 nM). In contrast, 7 alpha-halo-analogues were ineffective versus FPPS (IC50 > 600 microM), but inhibited Rab geranylgeranyl transferase (RGGT) (IC50 = 16-35 microM) similarly to 7 itself (IC50 = 24 microM). The alpha-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.

Original publication




Journal article


Journal of medicinal chemistry

Publication Date





5967 - 5975


Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.


Cell Line, Animals, Mice, Durapatite, Propionates, Diphosphonates, Etidronic Acid, Pyridines, Alkyl and Aryl Transferases, Chromatography, Liquid, Cell Proliferation, Cell Survival, Structure-Activity Relationship, Bone Density Conservation Agents, Geranyltranstransferase, Protein Prenylation, Organophosphonates