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

Abstract

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.

Oxytrofalcatins A–F, N-benzoylindole analogues from the roots of Oxytropis falcata (Leguminosae)

“…Moreover, compound 5 was found to be surprisingly stable. When a mixture of 5 and NaOH dissolved in MeOH/H 2 O was heated to reflux, no reaction products could be detected by TLC after 18 h (Dhanoa et al, 1993). In so far as N-acyl derivatives 1-6 are weaker bases than regular amines (Aggarwal et al, 2003), they did not give the typical color changes for alkaloids upon reaction with the Dragendorff reagent (Akhmedzhanova, 1996), providing additional support for the structures of compounds 1-6.…”

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

“…In particular, the carboxylic acid moiety has been of interest in biomolecular recognition. This concept can play a major role in the discovery of new non-peptidic angiotensin II antagonists [134]. Systematic evaluation of molecular metaphors for the replacement of the carboxylic acid moiety in Losartan, led to substitution with tetrazole, a more favourable anti-hypertensive profile, in comparison to its carboxylic acid congener [135].…”

Inhibitory Perspective of New Synthesized Compounds against Angiotensin Receptor: Schrodinger-based Induced-Fit Molecular Docking

“…Angiotensinogen and Ang-I are inert peptides without a known function. Other than Ang-II, angiotensins (Ang-III, Ang-IV, Ang (1-7)) are active peptides that are produced in small amounts and whose physiological relevance is unclear [12]. As a consequence, the RAS' physiologic functions are assumed to be mediated mostly by the highly active peptide Ang II.…”