Imidazole-5-acrylic acids: potent nonpeptide angiotensin II receptor antagonists designed using a novel peptide pharmacophore model

Abstract

A series of novel nonpeptide angiotensin II receptor antagonists containing a substituted (E)-acrylic acid has been developed. The overlay of 1, an imidazole-5-acetic acid found in the patent literature, on a novel pharmacophore model of AII suggested that extension of the acid side chain and attachment of a second aryl residue to mimic the C-terminal phenylalanine region of AII would lead to increased activity. A study of extended acid side chains at C-5 of the imidazole nucleus led to the discovery of the (E)-acrylic acid 5 as a promising starting point for further exploration. As predicted by the modeling, substitution of a benzyl group on the acrylic acid side chain to mimic the phenylalanine gave increased potency. An extensive study of the SAR of the newly introduced aromatic ring revealed that electron-rich heteroaryl rings provided improved activity, most notably in the in vivo rat models. Compound 40, (E)-3-[2-butyl-1- [(2-chlorophenyl)methyl]imidazol-5-yl]-2-[(2-thienyl)methyl]-2- propenoic acid, has been shown to be a potent, competitive, and orally active small molecule AT-1 receptor antagonist. It exhibits a 2 orders of magnitude increase in binding affinity and a 10-fold improvement in in vivo potency as compared to compound 1 and represents an important milestone in the development of even more potent nonpeptide angiotensin II receptor antagonists.

Acrylamide moiety, a Valuable Fragment in Medicinal Chemistry: Insight into Synthetic Methodologies, Chemical Reactivity and Spectrum of Biological Activities of Acrylamide Derivatives

“…Keenan 50 et al reported synthesis of a set of substituted (E) -acrylic acid derivatives for evaluation of their activity as angiotensin II receptor. They were guided by a developed pharmacophore model which suggests that the addition of acid chain and an aryl side chain to imidazole mimicking the C-terminal phenylalanine region of native ligand would lead to increased activity.…”

The Directed Ortho Metallation (DoM)–Cross‐Coupling Nexus. Synthetic Methodology for the Formation of Aryl–Aryl and Aryl–Heteroatom–Aryl Bonds

“…A DoM-Migita-Stille connection was established for the synthesis of 138, also undertaken for potential demonstration of angiotensin II antagonist activity (Scheme 14.28). Thus, the stannylated imidazole 134, derived by virtue of the 2-(trimethylsilyl)ethoxymethyl ether DMG, undergoes cross-coupling with the aryl triflate 135 under the standard Migita-Stille conditions to afford 136, which is further converted by conventional reactions into 138 [141]. Reversal of the tin and triflate groups of the cross-coupling partners, tested in related systems, was shown to provide higher yields.…”

Specific Nonpeptide Photoprobes as Tools for the Structural Study of the Angiotensin II AT1 Receptor

“…A more difficult but straightforward manner of investigating receptor topography consists of its covalent labeling with appropriate synthetic ligands, − as previously carried out with peptidic angiotensin II-derived probes. − The goal of the present study was to design the first AT 1 specific photoactivatable nonpeptide derivative. The strategy used for the development of these compounds was based on previous structure−function relationships and the prevision of appropriate synthetic schemes. − We investigated a new series of molecules potentially suitable for the introduction of an azido function selected as the photoactivatable group and easy to be obtained in a tritiated form. This series was designed according to the nonpeptide AT 1 receptor antagonist SKF 108566 18,21,22 (Figure ).…”