Hypoglycemic potential of cyclic guanidine derivatives

• Published in: Pure and applied chemistry Vol. 89; no. 8; pp. 1007 - 1016
• Main Authors: Spasov, Alexander A., Vassiliev, Pavel M., Lenskaya, Karina V., Anisimova, Vera A., Kuzmenko, Tatyana A., Morkovnik, Anatolii S., Kosolapov, Vadim A., Babkov, Denis A.
• Format: Journal Article
• Language: English
• Published: Berlin De Gruyter 01.08.2017; Walter de Gruyter GmbH
• Subjects: Aminobenzimidazole; Animals; Anticancer properties; Antidiabetics; computer-aided molecular design; Derivatives; diabetes; Diabetes mellitus; Guanidines; heterocyclic chemistry; Hypoglycemia; Insulin; Medical research; medicinal chemistry; Mendeleev XX; Metformin; Pharmacology; structure-activity; Toxicity
• ISSN: 0033-4545; 1365-3075
• DOI: 10.1515/pac-2016-1024

Guanidine derivatives are widely used antidiabetic drugs. Metformin (biguanide) is the first-line therapy for the type 2 diabetes mellitus due to its multi-target and pleiotropic effects. Compounds that comprise guanidine moiety integrated in a heterocycle, i.e. cyclic guanidines, represent an increasing area of interest. We have synthesized and studied hypoglycemic effects of a range of cyclic guanidines, namely 2-aminobenzimidazoles and structurally related imidazo[1,2- ]-, pyrimido[1,2- ]-, pyrrolo[1,2- ]-, triazolo[1,5- ]benzimidazole tricyclic derivatives. We have determined the potential of these scaffolds using molecular modeling and QSAR analysis. Experimental studies have shown that -(diethylamino)ethyl-2,3-dihydro-imidazo[1,2- ]benzimidazole (RU-254, diabenol) exhibits potent antidiabetic effects along with a low toxicity. We have found that diabenol exerts long-term glucose-lowering effects in prediabetic and diabetic animals, stimulates the first phase of insulin secretion and reduces the rate of liver glycogenolysis. Additionally, diabenol has been shown to exhibit antiplatelet, geroprotective and antitumor activities in animals. Clinical trials confirm that diabenol produces a range of antidiabetogenic effects such as improved glycemia, reduced HbA , stimulation of insulin secretion, decreased thrombogenic potential of blood and ameliorated hemorheology.