Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles

Article abstract of DOI:10.1021/jm00078a013

A series of N-acylated indoles (12-18), N-alkylated indoles (19-24), N- acylated dihydroindoles (26-30), and N-alkylated dihydroindoles (31-34) were synthesized and evaluated in the in vitro AT₁ (rabbit aorta) and AT₂ (rat midbrain) binding assay. The carboxylic acid 3-[[N-(2-carboxy-3,6- dichlorobenzoyl)-5-indolyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5- b)pyridine (14b) was found to be the most potent AT₁ (IC₅₀ = 0.8 nM) antagonist in the N-acylated indole series and displayed a 25-fold higher potency than the parent unsubstituted derivative 14a (AT₁ IC₅₀ = 20 nM) and a 22-fold greater potency than the corresponding dihydroindole analog 27 (AT₁ IC₅₀ = 18 nM). Replacement of the terminal carboxyl (COOH) of 14a with the bioisostere tetrazole in 16 (AT₁ IC₅₀ = 5 nM, AT₂ IC₅₀ = 130 nM) not only improved the AT₁ potency by 4-fold but also resulted in a 50- fold increase in AT₂ activity. In the N-alkylated indole series, the tetrazole 3-[[N-(2-tetrazol-5-yl-6-chlorobenzyl)-5-indolyl]methyl]-5,7- dimethyl-2-ethyl-3H-imidazo[4,5,-b]pyridine (24) exhibited the highest AT₁ (IC₅₀ = 1 nM) activity, revealing a 230-fold increase in AT₁ activity as a result of the incorporation of the isosteric tetrazole for the carboxyl (COOH) of 20 and a nearly 9-fold increase over the corresponding deschloro analog 22 (AT₁ IC₅₀ = 8.7 nM). Tetrazole 34 was identified as the most potent (AT₁ IC₅₀ = 18 nM) AT₁ receptor antagonist in a structurally distinct series of compounds derived from N-alkylation of dihydroindole 25. A new class of highly potent (14b, AT₁ IC₅₀ = 0.8 nM; 24, AT₁ IC₅₀ = 1 nM) AT₁-selective non-peptide AII receptor antagonists derived from N- substituted indoles and dihydroindoles is disclosed. Tetrazole 24 of the N- alkylated indole series displayed good in vivo activity by blocking the AII- induced pressor response for 5.5 h after intravenous administration in conscious normotensive rats at a 1.0 mg/kg dose level.