Synthesis and biological evaluation of α-halogenated bisphosphonate and phosphonocarboxylate analogues of risedronate

Mong S. Marma, Zhidao Xia, Charlotte Stewart, Fraser Coxon, James E. Dunford, Rudi Baron, Boris A. Kashemirov, Frank H. Ebetino, James T. Triffitt, R. Graham G. Russell, Charles E. McKenna

Research output: Contribution to journalArticlepeer-review

Abstract

α-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 α-OH group in 5 and 7 enhances bone affinity. The 5 α-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 (α-F) to 340 (α-Br) nM (5, 6 nM). In contrast, 7 α-halo-analogues were ineffective versus FPPS (IC 50 > 600 μM), but inhibited Rab geranylgeranyl transferase (RGGT) (IC50 = 16-35 μM) similarly to 7 itself (IC50 = 24 μM). The α-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.

Original languageEnglish (US)
Pages (from-to)5967-5975
Number of pages9
JournalJournal of medicinal chemistry
Volume50
Issue number24
DOIs
StatePublished - Nov 29 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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