Studies on quinazolines. 5. 2,3-Dihydroimidazo[1,2-c]quinazoline derivatives: a novel class of potent and selective .alpha.1-adrenoceptor antagonists and antihypertensive agents

Abstract

A series of 2-[(substituted phenylpiperazin-1-yl)methyl]- and 2-[(substituted phenylpiperidin-1-yl)methyl]-2,3-dihydroimidazo[1,2- c]quinazolin-5(6H)-ones or -5(6H)-thiones, and 3-[(substituted phenylpiperazin-1-yl)methyl]-2,3-dihydroimidazo[1,2-c]quinaz oline derivatives were synthesized, as conformationally restricted analogues of SGB-1534 and ketanserin, for evaluation as alpha-antagonists and antihypertensive agents. Most compounds containing a (substituted phenylipiperazinyl)methyl side chain displayed high binding affinity for alpha 1-adrenoceptor with no significant activity at alpha 2-sites. Compounds having a (substituted phenylpiperazinyl)methyl at the 3-position of 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ring system had a better activity than those with the same substituent at the 2-position. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented and indicate that compounds with substitution at the ortho position on the benzene ring of the phenylpiperazine side chain moiety are more potent than those without substitution and/or substitutions at the 3- and 4-positions. Computer-assisted superimposition of SGB-1534 and 20b showed little structural correspondence between the quinazolinone and 2,3-dihydroimidazo[1,2-c]quinazoline nucleus, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Antihypertensive activity was evaluated via intravenous administration of each compound to spontaneously hypertensive rats, and compounds (16a, 16b, 20b, and 28b) illustrated similar efficacy to SGB-1534 when assessed after 6 h. The pA2 value for 16a against phenylephedrine in rat aorta was much higher than that of prazosin. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compounds 20b and 28b warrant further evaluation.

A Novel Nonpeptide Ligand for Formyl Peptide Receptor-Like 1

“…However, this nonpeptide ligand for FPRL1 may serve as the nucleus for further structural modifications leading to the discovery of more potent and efficacious agonists. Based on published data, it is possible to develop quinazolinone derivatives with higher binding affinities for cell surface receptors including GPCRs (Oshita et al, 1986;Chern et al, 1993;Padia et al, 1998). The selective activation property of Quin-C1 will be of particular interest for future development of small molecular weight, nonpeptide compounds devoid of cell-stimulating functions associated with tissue injury.…”

Analytical and biological characterization of quinazoline semicarbazone derivatives

“…1,2,3,5-tetrahydro imidazo [2,1-b] quinazoline as antihypertensive agent (Loev et al, 1971). 5-2,3 dihydro imidazo [1,2-c] quinazoline derivatives as potent and selective a 1 -adrenoceptor antagonists and antihypertensive agents (Chern et al, 1993). A novel class of 6-thiazolyl quinazolines as selective inhibitors of both ErbB-2 and EGFR tyrosine kinase activity was reported (Gaul et al, 2003).…”

Portal Hypotensive Effects of DL-028 and Prazosin on Portal Hypertensive Rats

“…Receptor-binding studies indicated that the affinity constant (K i ) of DL-028 for · 1 -adrenoceptors is around 2 ! 10 -10 mol/l, and its affinity for · 1 -receptors is more than 2,000-fold greater than that for · 2 -receptors [13]. In the present study, we assessed the hemodynamic effects of both DL-028 and prazosin in portal hypertensive rats.…”

“…For each dose of either drug, it was confirmed that infusion of vehicle (1% dimethyl sulfoxide) did not alter any of the hemodynamic parameters (tables 1, 2). Drugs DL-028 was synthesized and characterized as described in a previous paper [13]. Prazosin was purchased from Sigma Chemical Co. (St. Louis, Mo., USA).…”

“…, is a synthetic · 1 -adrenoceptor antagonist with a potent antihypertensive effect in spontaneously hypertensive rats [13]. Its molecular weight is 409.6, with an empirical formula C 22 H 27 N 5 O 2 ( fig.…”