152147-96-1Relevant academic research and scientific papers
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
Mojarrad, J. Shahbazi,Nazemiyeh,Kaviania
experimental part, p. 171 - 179 (2010/10/21)
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.
Syntheses of substituted pyrrolo[2,3-d]imidazole-5-carboxylates and substitued pyrrolo[3,2-d]imidazole-5-carboxylates
Shafiee,Mojarrad, J. Shabhbazi,Jalili,Adhami,Hadizadeh
, p. 367 - 373 (2007/10/03)
Starting from readily available p-substituted-benzylamines a series of ethyl 2-alkylthio-1-substituted-benzylpyrrolo[2,3-d]imidazole-5-carboxylates was prepared. In addition, starting from 2-alkyl-4(or 5)-formylimidazoles and methyl 4′-bromomethylbiphenyl-2-carboxylate a series of methyl substituted-pyrrolo[2,3-d]imidazole-5-carboxylates and methyl substituted-pyrrolo[3,2-d]imidazole-5-carboxylates was prepared.
Potent Nonpeptide Angiotensin II Receptor Antagonists. 2. (1-Carboxybenzyl)imidazole-5-acrylic Acids
Keenan, Richard M.,Weinstock, Joseph,Finkelstein, Joseph A.,Franz, Robert G.,Gaitanopoulos, Dimitri E.,et al.
, p. 1880 - 1892 (2007/10/02)
The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J.Med.Chem. 1992, 35, 3858).Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II.Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity.SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency.Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented.The parent diacid analog, SKF 108566 or (E)-3--2-propenoic acid, is currently in clinical development for the treatment of hypertension.
