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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

DOI

10.1021/jm0702884

Type

Journal article

Journal

J Med Chem

Publication Date

29/11/2007

Volume

50

Pages

5967 - 5975

Keywords

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