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

• Published in: Journal of medicinal chemistry 1993-12, Vol.36 (26), p.4230-4238
• Main Authors: Dhanoa, Daljit S, Bagley, Scott W, Chang, Raymond S. L, Lotti, Victor J, Chen, Tsing Bau, Kivlighn, Salah D, Zingaro, Gloria J, Siegl, Peter K. S, Patchett, Arthur A, Greenlee, William J
• Format: Article
• Language: English
• Subjects: 1-Sarcosine-8-Isoleucine Angiotensin II - metabolism; Acylation; Alkylation; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Aorta - metabolism; Benzoates; Blood Pressure - drug effects; Drug Design; Imidazoles - chemical synthesis; Imidazoles - metabolism; Imidazoles - pharmacology; Indoles - chemical synthesis; Indoles - metabolism; Indoles - pharmacology; Kinetics; Mesencephalon - metabolism; Molecular Structure; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - pharmacology; Rabbits; Rats; Receptors, Angiotensin - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• 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-dimeth yl- 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.