Dihydropyrimidine angiotensin II receptor antagonists

Abstract

The discovery of the nonpeptide angiotensin II (AII) receptor antagonist losartan, previously called DuP 753, has stimulated considerable interest in the synthesis of novel analogs of this compound. Our efforts in this area have resulted in the discovery of dihydropyrimidines as potent AII receptor antagonists. The chemistry leading to this novel class of AII antagonists and their biological properties are reported in this publication. Structure-activity studies showed that a variety of substituents are tolerated on the dihydropyrimidine ring, indicating that the AII receptor is permissive in accepting this region of the nonpeptide antagonists. As reported for imidazole-based AII antagonists, the tetrazolyl dihydropyrimidine analogs were found to be more potent than the corresponding carboxylic acids. Our studies show that dihydropyrimidine analogs 2-butyl-4-chloro-1,6-dihydro-6-methyl-1-[[2'-(1H-tetrazol-5-yl)[1, 1'-biphenyl]-4-yl]methyl]pyrimidine-5-carboxylic acid, ethyl ester (Ki = 8.3 nM), 2-butyl-4-chloro-1,6-dihydro-6-methyl-1- [[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5- pyrimidinecarboxylic acid (Ki = 1.0 nM), and 2-butyl-6-chloro-1,4-dihydro-4,4-dimethyl-1-[[2'-(1H-tetrazol-5-yl )[1,1'- biphenyl]-4-yl]methyl]-5-pyrimidinecarboxylic acid, ethyl ester (Ki = 1.1 nM), display affinities for the AII receptor which are comparable to or better than losartan (Ki = 9.0 nM). One of these derivatives, 2-butyl-4-chloro-1,6-dihydro-6-methyl-1-[[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]pyrimidine-5-carboxylic acid, ethyl ester, showed antihypertensive activity on oral administration to spontaneously hypertensive rats. These results demonstrate that the imidazole of losartan can be successfully replaced with a dihydropyrimidine ring.

Synthesis and Characterization of Novel Biginelli Dihydropyrimidinone Derivatives Containing Imidazole Moiety

“…To prepare the final dihydropyrimidinone derivatives, a mixture of substituted benzaldehyde (0.01 mol) III, enaminone (II) (0.01 mol), urea (0.01 mol) IV, and glacial acetic acid (10 mL) was heated under reflux for 3 hours. e precipitates of compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) were collected by vacuum filtration. e product was washed several times with water and recrystallized from glacial acetic acid and ethanol mixture.…”

“…Pyrimidines have played an important role in the medicinal chemistry [7]. Pyrimidines are important scaffold in the field of medicinal chemistry because of their potential biological activities such as antitumor, antivirus, and antibacterial agents [8]. 4-Aryl-1,4-dihydropyridines like nifedipine was first introduced as antihypertensive into clinical medicine in 1975.…”

C-Terminal 1-Aminoethyltetrazole-Containing Oligopeptides as Novel Alanine Racemase Inhibitors

“…Due to these factors, there is scope for the development of a new series of AlaR inhibitors. The tetrazole moiety has been utilised as a bioisostere for carboxylic acids in drugs such as Losartan, where problems occurred with membrane permeability earlier in the development cycle [8]. Thus, to see if a tetrazole bioisoteric replacement would produce interesting activity against AlaR in intact bacteria, l-1-aminoethyltetrazole 4a-L was prepared and studied as an alanine (3) bioisostere ( Figure 2).…”

Synthesis of 3‐[4‐Acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as Novel Potassium Channel Openers

“…[1][2][3][4] KCO's hold therapeutic promise as antianginals, cardioprotectives, bronchodilators, and agents against urinary incontinence. [5][6][7][8][9][10][11][12] Some KCO's have been introduced in the clinic as antihypertensive agents. Cromakalim ((±)-1) is a prototype KCO, 2 which lacks tissue selectivity, therefore, limiting its clinical potential.…”