Design and Synthesis of New Tetrazolyl- and Carboxy-biphenylylmethyl-quinazolin-4-one Derivatives as Angiotensin II AT₁ Receptor Antagonists

Abstract

A series of novel quinazolin-4-ones was designed and their molecular modeling simulation fitting to a new HipHop 3D pharmacophore model using CATALYST was examined. Several compounds showed significant high simulation fit values. The designed compounds were synthesized and eight of them were biologically evaluated in vitro using an AT1 receptor binding assay, where compound XX competed weakly against radiolabeled Sar1Ile8-angiotensin II (Ang II) binding, compounds XIV and XXII showed moderate competition, and compound XXV showed almost equal ability to displace radiolabeled Sar1Ile8-Ang II binding to AT1 receptors as losartan. In vivo biological evaluation study of compounds XIV, XXII, and XXV on both normotensive and hypertensive rats revealed that compound XXV demonstrated higher hypotensive and antihypertensive activity than the reference compound losartan. To obtain a highly active compound from a candidate set of only eight tested compounds illustrates the power and utility of our pharmacophore model.

ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents

“…The low percentage of the retrieved molecules of the databases proved the high selectivity of such hypothesis. 21 In addition, it was found that the ACEI molecules; 3, 4, and 5 ( Fig. 1), that exist among the used databases molecules, were among the recognized mapped molecules in this search.…”

Facile One-Pot Synthesis of Quinazoline-2,4-dione Derivatives and Application to Naturally Occurring Alkaloids from Zanthoxylum Arborescens

“…Quinazoline-2,4-diones are one of the important heterocycles 1 and have been shown to possess pharmacologically interesting properties such as anti-hypertensive, 2 antidiabetic, 3 and immunosuppressive activities. 4 Among these, synthetic pelanserine (TR2515) (1) 5 is a well established potent anti-hypertensive, having activity comparable to ketanserin, 6 which is an anti-hypertensive agent used clinically.…”

An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT1 Angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies

“…The discovery by DuPont of the first potent and orally active non-peptide AII antagonist losartan [10] has stimulated extensive research interest in this area. Several patents and publications have appeared over the past few years [11,12] describing new AII receptor antagonists including candesartan, irbesartan, valsartan, telmisartan, tasosartan and eprosartan, which have been proven safe and effective in the treatment of hypertension and other cardiovascular disorders [13][14][15][16][17][18][19][20][21].…”