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Synthesis andin VitroEvaluation of N-[[4-[2-(Carboxyl)-1-Cycloalken-1-yl]Phenyl]Methyl]Imidazoles as Nonpeptide Angiotensin II Receptor Antagonists

1993; Wiley; Volume: 40; Issue: 3 Linguagem: Inglês

10.1002/jccs.199300041

2192-6549

Ho‐Shen Lin, Ashraff Rampersaud, Kathy Zimmerman, Mitchell I. Steinberg, Donald B. Boyd,

Receptor Mechanisms and Signaling

Abstract 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.