title: 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.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA. mckenna@usc.edu
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.forename: Boris A
authors.initials: BA
authors.lastname: Kashemirov
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Błazewska
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mallard-Favier
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Stewart
authors.forename: Javier
authors.initials: J
authors.lastname: Rojas
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lundy
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ebetino
authors.forename: Rudi A
authors.initials: RA
authors.lastname: Baron
authors.forename: James E
authors.initials: JE
authors.lastname: Dunford
authors.forename: Marie L
authors.initials: ML
authors.lastname: Kirsten
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
authors.forename: Joy L
authors.initials: JL
authors.lastname: Bala
authors.forename: Mong S
authors.initials: MS
authors.lastname: Marma
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007773:Lactates / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D010024:Osteoporosis / Q000188:drug therapy; D017368:Protein Prenylation / Q000187:drug effects; D000068296:Risedronic Acid; D013237:Stereoisomerism; D020691:rab GTP-Binding Proteins
chemical_list: C549922:2-hydroxy-3-imidazo(1,2-a)pyridin-3-yl-2-phosphonopropionic acid; D050071:Bone Density Conservation Agents; D004791:Enzyme Inhibitors; D007773:Lactates; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C003128:beta-phosphonopropionic acid; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; C083291:geranylgeranyltransferase type-I; D020691:rab GTP-Binding Proteins; D000068296:Risedronic Acid; D012968:Etidronic Acid