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Synthesis and Regioselective Hydrolysis of Novel Dialkyl 4-Imidazolyl-1,4-Dihydropyridine-3,5-dicaroxlates as Potential Dual Acting Angiotensin II Inhibitors and Calcium Channel Blockers

J. Shahbazi Mojarrad^a,*, H. Nazemiyeh^b and F. Kaviani^a

^aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
^bDepartment of Pharmacognosy and Food Science, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

Most of the known effects of angiotensin II are mediated via AT₁ receptor by increasing intracellular Ca²⁺ by influx of extracellular Ca²⁺. Combination therapies of angiotensin receptor blocker (ARB) with calcium channel blocker (CCB) which act through L-type calcium channel have beneficial therapeutic and protective effects on cardiovascular system. Thus, it was hypothesized that merging the key structural elements present in an AT₁ receptor antagonist (telmisartan) with key structural elements in 1,4-dihydropyridine calcium channel blockers (nifedipine) would yield a compound with dual activity for both receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[(2΄-carboxybiphenyl-4-yl)methyl]imidazole-4(or 5)-yl]-3,5-pyridinedicarboxylates (4 and 6). The synthesis of compounds 4 and 6 was accomplished through the reaction of 2-n-alkyl-1-[(2΄-carbomethoxybiphenyl-4-yl)methyl]imidazole-4(or 5)-carboxaldehydes with alkyl acetoacetate followed by regioselctive  hydrolysis of carboethoxybiopheny to carboxybiphenyl that are essential for ARB activity. It is suggested that existence of hindrance by substituted groups prevent hydrolysis of esteric groups on dihydropyridine ring. The structures of the compounds were characterized by ¹H-nuclear magnetic resonance, infrared and mass spectroscopy.

Keywords: Dual mechanism, Angiotensin II antagonist, Calcium channel blocker, 1,4-Dihydropyridine