On the basis of previous studies, we identified pyrazine-pyridine A as a potent vascular endothelial growth factor inhibitor and pyrimidine-pyridine B as a moderately potent cyclin dependent kinase (CDK) inhibitor. A proposed combination of CGP-60474 and compound B led to the discovery of [1,3,5]triazine-pyridine as a new series of potent CDK inhibitors. Palladium-catalyzed C-C bond formation reactions, particularly the Negishi coupling reaction, were used to assemble various triazine-heteroaryl analogues effectively. Among them, compound 20 displayed high inhibitory potency at CDK1 (IC(50) = 0.021 microM), CDK2, and CDK5 and submicromolar potency at CDK4, CDK6, and CDK7. Compound 20 also displayed high potency at GSK-3beta. It demonstrated potent antiproliferative activity on various tumor cell lines, including HeLa, HCT-116, U937, and A375. When 20 was administered intraperitoneally at 150 and 125 mg/kg to nude mice bearing human A375 xenografts, the compound produced a significant survival increase. Molecular docking studies were conducted in an attempt to enhance the understanding of the observed structure-activity relationship.

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

Mitochondria targeting by guanidine- and biguanidine-porphyrin photosensitizers.

Arylpiperazines are nonselective agents that bind at 5-HT3 serotonin receptors with moderate to high affinity, whereas 1-phenylbiguanide is a low-affinity but more selective 5-HT3 agonist. In an at...

Structure−Activity Relationships for the Binding of Arylpiperazines and Arylbiguanides at 5-HT3 Serotonin Receptors

Arylguanidine and arylbiguanide binding at 5-HT3 serotonin receptors: A QSAR study

The efficient preparation and pharmacological characterization of different families of (bis)guanidine and (bis)2-aminoimidazoline derivatives ("twin" and "half" molecules) as potential alpha(2)-adrenoceptor antagonists for the treatment of depression is presented. The affinity toward the alpha(2)-adrenoceptor of all the compounds prepared was measured in vitro in human brain tissue. Additionally, the activity as agonist or antagonist of those compounds with a pK(i) larger than 7 was determined in functional [(35)S]GTPgammaS binding assays in human brain tissue. Finally, the activity of the most promising compounds was confirmed by means of in vivo microdialysis experiments in rats. Compounds 1, 2b, 3b, 12b, 13b, 17b, 18b, 22b, 25b, 26b, 28b, and 30 showed a good affinity toward the alpha(2)-ARs. In general, the 2-aminoimidazoline derivatives displayed higher affinities than their guanidine analogues. Finally and most importantly, compounds 18b and 26b showed antagonistic properties over alpha(2)-ARs not only in vitro [(35)S]GTPgammaS binding but also in vivo microdialysis experiments. Moreover, both compounds have shown to be able to cross the blood-brain barrier and, therefore, they can be considered as potential antidepressants.

Guanidine and 2-aminoimidazoline aromatic derivatives as alpha(2)-adrenoceptor antagonists, 1: toward new antidepressants with heteroatomic linkers.

A series of aromatic guanidines and several 1-phenylbiguanides was prepared and tested for cardiovascular (CV) effects in anesthetized dogs measuring heart rate, blood pressure, carotid artery blood flow, and myocardial force changes. The predominant CV effect at minimally effective dose was vasoconstriction unassociated with cardiac stimulation. The structure-activity relationships of the compounds were discussed comparing their structural similarities to the beta-phenylethylamines. The most potent members of the series were phenylguanidines substituted in the 3 and 4 positions on the aromatic nucleus with hydroxy or chloro groups. Preliminary mechanism studies indicated that the 3,4-dihydroxyphenylguanidines act at least partially by a direct alpha-adrenergic mechanism

R. C. Liu

Papers

Cardiovascular activity of aromatic guanidine compounds.

Cardiovascular activity of aromatic guanidine compounds