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.

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 9 Pg. 3454-64 (May 13 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20394422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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