The Therapeutic Potential of Benzimidazoles

**73**

**Chapter 5**

**Abstract**

acteristic for N9

**1. Introduction**

Benzimidazoles

*and Olga N. Zhukovskaya*

Antidiabetogenic Features of

*Alexander A. Spasov, Pavel M. Vassiliev, Vera A. Anisimova* 

Literature data on the insulinogenic effect of 2-aminobenzimidazole prompted us to investigate its novel derivatives, particularly those containing an additional fused cycle in C1,2-α position, including imidazole, dihydroimidazole, or tetrahydropyrimidine ring. Consensus analysis of the hypoglycemic effect of these compounds performed with IT Microcosm and PASS system revealed that activity is mostly char-

analysis of hypoglycemic activity identified substituents that determine the greatest pharmacological effect. According to the in silico assessment of the ADME properties, RU-254 was nominated as a lead compound due to the most optimal calculated and experimental activity and pharmacokinetic parameters. Preclinical studies have shown that identified compound has a pronounced insulinogenic effect and hypoglycemic effect, both in intact animals and in animals with experimental diabetes mellitus. RU-254 also reduces the level of glycated hemoglobin upon chronic administration, slightly decreases the activity of DPP-4, and increases the average number of Langerhans islets in the pancreas. Pharmaceutical drug formulation of RU-254 was developed and investigated for pharmacokinetic, pharmacodynamic, and toxicological properties. The dosage form of the drug under the name limiglidol (compound RU-254, diabenol) was evaluated in the full cycle of clinical studies that confirmed the safety, tolerability, and prominent antidiabetic properties of the drug.

**Keywords:** in silico, IT Microcosm, consensus prediction, antidiabetic effect,

The history of drug discovery for the treatment of diabetes mellitus was and still is strongly determined by achievements in the field of fundamental medicine. Initially, the role of the pancreas and islets of Langerhans in the development of this pathology was proved; later, the structure of insulin, insulin receptor, and glucose transporters was deciphered; the role of the liver glycogenolysis and gluconeogenic enzymes, contributing to increased glucose output and hyperglycemia, was established; molecular mechanisms for the development of insulin resistance, the

and intestinal α-glucosidase were revealed, which led to the introduction of novel

/glucose transporters in the kidneys,

aminobenzimidazoles, cyclic benzimidazoles, pharmacodynamics,

pharmacokinetics, toxicology, diabenol

importance of the incretin system and Na+

antidiabetic drugs into clinic [1–4].


#### **Chapter 5**
