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3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC, 1) is a phosphonocarboxylate (PC) analogue of 2-(3-pyridyl)-1-hydroxyethylidenebis(phosphonic acid) (risedronic acid, 2), an osteoporosis drug that decreases bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) in osteoclasts, preventing protein prenylation. 1 has lower bone affinity than 2 and weakly inhibits Rab geranylgeranyl transferase (RGGT), selectively preventing prenylation of Rab GTPases. We report here the synthesis and biological studies of 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC, 3), the PC analogue of minodronic acid 4. Like 1, 3 selectively inhibited Rab11 vs. Rap 1A prenylation in J774 cells, and decreased cell viability, but was 33-60x more active in these assays. After resolving 3 by chiral HPLC (>98% ee), we found that (+)-3-E1 was much more potent than (-)-3-E2 in an isolated RGGT inhibition assay, approximately 17x more potent (LED 3 microM) than (-)-3-E2 in inhibiting Rab prenylation in J774 cells and >26x more active in the cell viability assay. The enantiomers of 1 exhibited a 4-fold or smaller potency difference in the RGGT and prenylation inhibition assays.

Original publication

DOI

10.1021/jm900232u

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

05/2010

Volume

53

Pages

3454 - 3464

Addresses

Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA. mckenna@usc.edu

Keywords

Cell Line, Humans, Osteoporosis, Bone Resorption, Lactates, Organophosphorus Compounds, Etidronic Acid, rab GTP-Binding Proteins, Alkyl and Aryl Transferases, Enzyme Inhibitors, Chromatography, High Pressure Liquid, Cell Survival, Stereoisomerism, Bone Density Conservation Agents, Protein Prenylation, Organophosphonates, Risedronate Sodium