Nimodipine: synthesis and metabolic pathway.
Key step of the synthesis of the calcium antagonistic cerebral vasodilator (+/-) isopropyl-2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (Bay e 9736, nimodipine) (5) is the cyclizing Michael addition of 3 onto 4. A pharmacokinetic study with 14C-nimodipine in the rat revealed as major metabolites the dihydropyridines 6 and 8 as well as the pyridines 7, 9, 10, 11, 13 and 14. A potential metabolic pathway is discussed involving ether cleavage and oxidation to the pyridine form as primary biotransformation steps. Reference metabolites were synthesized using 1,4-dihydropyridines with appropriate functionalities as precursors.
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004586:Electrophoresis; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D008297:Male; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000652:urine; D009553:Nimodipine; D051381:Rats; D011919:Rats, Inbred Strains
D009539:Nicotinic Acids; D009553:Nimodipine