Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids

Abstract

The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem. 1992, 35, 3858). Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II. Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity. SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency. Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented. The parent diacid analog, SK&F 108566 or (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazole-5-yl]-2-[(2- thienyl)methyl]propenoic acid, is currently in clinical development for the treatment of hypertension.

Highly Potent Modulation of GABAA Receptors by Valerenic Acid Derivatives

“…Treatment of primary amide 6 with oxalyl chloride/DMF in THF [10] provided nitrile 9 (Scheme 1), which could be further elaborated into tetrazole 10 in 64 % yield by heating with in situ prepared Bu 3 SnN 3 [11] at 100 8C for 6 days. A number of azide sources were investigated for the cycloaddition reaction with 7, but Bu 3 SnN 3 proved to be the most efficient with regard to yield and purity of the product, even though the reaction was very slow and took several days to go to comple-tion.…”

Design of CID-cleavable protein cross-linkers: identical mass modifications for simpler sequence analysis

“…23 A Knoevenagel condensation with diethyl malonate introduced the required ester, and subsequent reduction with sodium borohydride selectively removed the reactive alkene to give diester 28 . 24,25 The esters were hydrolyzed with potassium hydroxide. A decarboxylative Mannich addition led to the desired acrylic acid 29 .…”

Predicting 3H-1,2,4-triazolinones as angiotensin II receptor antagonists: 2D and 3D QSAR by kNN-molecular field analysis approach

“…The pioneering efforts of the DuPont Group have generated a promising first non-peptide AT 1 antagonist losartan, which represent the prototype of the sartans. In the last decades several selective antagonists have been designed developed and are used to treat both hypertension and damage associated with the diseases such as arthrosclerosis and diabetes (Bernhart et al, 1993;Buhl Mayer et al, 1994;Ellingboe et al, 1994;Judd et al, 1994;Keenan et al, 1993;Kubo et al, 1993;Middlemiss et al, 1991;Ries et al, 1993;Salimbeni et al, 1995;Wong et al, 1990;Yanagisawa et al, 1996).…”