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.
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.
McKenna
Charles E
CE
Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA. mckenna@usc.edu
Kashemirov
Boris A
BA
Błazewska
Katarzyna M
KM
Mallard-Favier
Isabelle
I
Stewart
Charlotte A
CA
Rojas
Javier
J
Lundy
Mark W
MW
Ebetino
Frank H
FH
Baron
Rudi A
RA
Dunford
James E
JE
Kirsten
Marie L
ML
Seabra
Miguel C
MC
Bala
Joy L
JL
Marma
Mong S
MS
Rogers
Michael J
MJ
Coxon
Fraser P
FP
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
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