Design and Synthesis of Novel α_1a Adrenoceptor-Selective Antagonists. 1. Structure−Activity Relationship in Dihydropyrimidinones

Abstract

Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.

Synthesis, characterization, crystal and molecular structure analysis of N-(2,4-dimethylphenyl)-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

“…Biginelli's DHPM synthesis was further studied by Folkers and Johnson [2], Hinkel and Hey [3], Sweet and Fissekis [4] and Kappe [5]. Dihydropyrimidines of the Biginelli type are inherently asymmetric molecules and the influence of the absolute configuration at the stereogenic center at C 4 on biological activity is well documented [6][7][8][9][10][11]. DHPM's have emerged as calcium channel blockers [12], anti-hypertensive [13], anti-aggregating [14], antiviral [15], anti-tumor [16] and cardiovascular [17] agents.…”

Synthesis of 5-acetyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione and structural characterization of its polymorphs and complexes with 12-group metal iodides

“…Refluxing ZnI 2 or CdI 2 and the ligand in ethanol produced colorless crystals of diiodo(5-acetyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione)zinc (3) and diiodobis(5-acetyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione)cadmium (4). Reaction of HgI 2 with 2 in acetone-water mixture at room temperature gave tetraiodobis(5-acetyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione)dimercury (5).…”

“…Much of this interest has arisen from the multifaceted pharmacological profiles of such heterocycles. For example, esters of 4-aryl-2-oxo (or thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids (Z = COOR 0 ) have emerged as orally active antihypertensive agents [1,2], mitotic kinesin Eg5 inhibitors [3], a 1a adrenoceptor-selective antagonists [4], etc. Similar pharmacological properties were established for amides of 4-aryl-2-oxo(or thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids (Z = CONR 0 2 ) and 4-aryl-5-nitro-1,2,3,4-tetrahydropyrimidin-2-ones (Z = NO 2 ) [5].…”

“…Simplicity of the synthesis and high yields of the target products allow obtaining them in large quantities and studying various properties including complexing ability. In the present work, we report synthesis and X-ray diffraction analysis of a representative example of 5-acylsubstituted pyrimidines 1, 5-acetyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione (2), and its complexes with 12-group metal iodides (3)(4)(5).…”

Exploring the binding mechanism of dihydropyrimidinones to human serum albumin: Spectroscopic and molecular modeling techniques

“…Furthermore, they have attracted considerable interest in recent years because of their medicinally important as calcium channel blockers [1], antihypertensive agents [1], ␣1a-antagonists [2], mitotic kinesin Eg5 inhibitors [3], melanin concentrating hormone receptor antagonists [4], neuropeptide antagonists [5,6] and strong resistance HIVgp120-CD4 function [7]. Moreover, several alkaloids containing the dihydropyrimidinones as a core unit have been isolated from marine source, which also showed interesting biological properties [8].…”