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Synthesis and in Vitro Evaluation of N‐[[4‐[2‐(Carboxyl)‐1‐Cycloalken‐1‐yl]Phenyl]Methyl]Imidazoles as Nonpeptide Angiotensin II Receptor Antagonists
Author(s) -
Lin HoShen,
Rampersaud Ashraff A.,
Zimmerman Karen,
Steinberg Mitchell I.,
Boyd Donald B.
Publication year - 1993
Publication title -
journal of the chinese chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.329
H-Index - 45
eISSN - 2192-6549
pISSN - 0009-4536
DOI - 10.1002/jccs.199300041
Subject(s) - chemistry , moiety , stereochemistry , imidazole , steric effects , aryl , ring (chemistry) , alkylation , lipophilicity , angiotensin receptor , tetrazole , palladium , receptor , angiotensin ii , medicinal chemistry , organic chemistry , biochemistry , alkyl , catalysis
A series of nonpeptide angiotensin II receptor antagonists was synthesized via palladium‐assisted cross coupling of aryl stannane and cycloalkenyl triflates and subsequent alkylation of silyl‐protected imidazole. Our compounds, which have a terminal five‐ to seven‐membered cycloalkenyl ring, are compared to DuPont EXP7711, an N ‐[(2′‐carboxybiphenylyl)methyl]imidazole, which has a terminal phenyl moiety. Physicochemical properties of the compounds, such as lipophilicity, steric bulk, conformation, and the relative spatial proximity of the 2‐carboxyl and the middle phenyl, are quantitated by computational chemistry. Potency in terms of binding affinity to AT 1 receptors in rat adrenal glomerulosa and rabbit aorta is maximized when the terminal ring is aromatic.