Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid

Charles E McKenna; Boris A Kashemirov; Katarzyna M Błazewska; Isabelle Mallard-Favier; Charlotte A Stewart; Javier Rojas; Mark W Lundy; Frank H Ebetino; Rudi A Baron; James E Dunford; Marie L Kirsten; Miguel C Seabra; Joy L Bala; Mong S Marma; Michael J Rogers; Fraser P Coxon

doi:10.1021/jm900232u

Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid

J Med Chem. 2010 May 13;53(9):3454-64. doi: 10.1021/jm900232u.

Authors

Charles E McKenna¹, Boris A Kashemirov, Katarzyna M Błazewska, Isabelle Mallard-Favier, Charlotte A Stewart, Javier Rojas, Mark W Lundy, Frank H Ebetino, Rudi A Baron, James E Dunford, Marie L Kirsten, Miguel C Seabra, Joy L Bala, Mong S Marma, Michael J Rogers, Fraser P Coxon

Affiliation

¹ Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA. mckenna@usc.edu

PMID: 20394422
DOI: 10.1021/jm900232u

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Bone Density Conservation Agents / chemical synthesis
Bone Density Conservation Agents / pharmacology
Bone Resorption / drug therapy
Cell Line
Cell Survival / drug effects
Chromatography, High Pressure Liquid
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Etidronic Acid / analogs & derivatives
Etidronic Acid / pharmacology
Etidronic Acid / therapeutic use
Humans
Lactates / chemical synthesis
Lactates / pharmacology*
Lactates / therapeutic use
Organophosphonates / chemical synthesis
Organophosphonates / pharmacology*
Organophosphonates / therapeutic use
Organophosphorus Compounds / chemical synthesis
Organophosphorus Compounds / pharmacology*
Organophosphorus Compounds / therapeutic use
Osteoporosis / drug therapy
Protein Prenylation / drug effects
Risedronic Acid
Stereoisomerism
rab GTP-Binding Proteins

Substances

2-hydroxy-3-imidazo(1,2-a)pyridin-3-yl-2-phosphonopropionic acid
Bone Density Conservation Agents
Enzyme Inhibitors
Lactates
Organophosphonates
Organophosphorus Compounds
beta-phosphonopropionic acid
Alkyl and Aryl Transferases
Rab geranylgeranyltransferase
geranylgeranyltransferase type-I
rab GTP-Binding Proteins
Risedronic Acid
Etidronic Acid