Abstract
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity.
Highlights
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus
We present a new chemical type of GK activators (GKAs)
Interaction of 2 with Na2S or Na2S2 in the presence of catalytic amounts of tert-butyl ammonium bromide (TBAB) in a heterophase H2O-CHCl3 medium led to dimers 3 and 4, respectively
Summary
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity. The main goal in treatment of diabetes is the control of the blood glucose level This goal can be achieved with the injections of insulin in case of type 1 diabetes. The design and discovery of novel chemotypes of GKAs which do not possess such disadvantages is of a great interest for the pharmaceutical industry[12]
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