Bisphosphonates that inhibit the enzyme farnesyl diphosphate synthase (FDPS) are used for treatment of patients with osteoporosis and multiple myeloma. However, there is evidence that these drugs express their pharmacological effects through depletion of the downstream isoprenoid geranylgeranyl diphosphate (GGPP). Therefore inhibition of geranylgeranyl diphosphate synthase (GGDPS), the enzyme that mediates formation of GGPP from FPP and IPP, may offer a more direct way to achieve the biological effects desired from FDPS inhibition. In an effort to inhibit GGDPS several isoprenoid bisphosphonates have been made and tested, and some show IC50 values as low as 45 nM (1). Previous efforts focused on the formation of individual olefin isomers and comparison of their activity. However, the mixture of olefin isomers showed more potent biological activity than either of the individual isomers. Based on those findings, current work is focused on design and synthesis of analogues with increased biological activity. The details of the synthesis of novel bisphosphonates similar to compound 1, and their activity as inhibitors of GGDPS, will be presented.

Novel isoprenoid triazole bisphosphonates as potential GGDPS inhibitors

254th National Meeting (2017)

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