1-[(Imidazolidin-2-yl)imino]indazole. Highly alpha 2/I1 selective agonist: synthesis, X-ray structure, and biological activity

• Published in: Journal of medicinal chemistry 2008-06, Vol.51 (12), p.3599-3608
• Main Authors: Saczewski, Franciszek, Kornicka, Anita, Rybczyńska, Apolonia, Hudson, Alan L, Miao, Shu Sean, Gdaniec, Maria, Boblewski, Konrad, Lehmann, Artur
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-2 Receptor Agonists; Animals; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Blood Pressure - drug effects; Brain - metabolism; Crystallography, X-Ray; Heart Rate - drug effects; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; Imidazoline Receptors - agonists; Imidazoline Receptors - chemistry; In Vitro Techniques; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Injections, Intravenous; Male; Models, Molecular; Molecular Structure; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Adrenergic, alpha-2 - chemistry; Static Electricity; Structure-Activity Relationship; Thermodynamics
• ISSN: 0022-2623
• DOI: 10.1021/jm800112s

Novel benzazole derivatives bearing a (imidazolidin-2-yl)imino moiety at position 1 or 2 were synthesized by reacting 1-amino- or 2-aminobenzazoles with N, N'-bis( tert-butoxycarbonyl)imidazolidine-2-thione in the presence of HgCl 2. Structures of 1-[(imidazolidin-2-yl)imino]indazole (marsanidine, 13a) and free base of the 4-Cl derivative 12e were confirmed by X-ray single crystal structure analysis. Compound 13a was found to be the selective alpha 2-adrenoceptor ligand with alpha 2-adrenoceptor/imidazoline I 1 receptor selectivity ratio of 3879, while 1-[(imidazolidin-2-yl)imino]-7-methylindazole ( 13k) proved to be a mixed alpha 2-adrenoceptor/imidazoline I 1 receptor agonist with alpha 2/I 1 selectivity ratio of 7.2. Compound 13k when administered intravenously to male Wistar rats induced a dose-dependent decrease in mean arterial blood pressure (ED50 = 0.6 microg/kg) and heart rate, which was attenuated following pretreatment with alpha 2A-adrenoceptor antagonist RX821002. Compound 13a may find a variety of medical uses ascribed to alpha 2-adrenoceptor agonists, and its 7-methyl derivative 13k is a good candidate for development as a centrally acting antihypertensive drug.