2. Academic Validation
  3. Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

  • Sci Rep. 2017 Nov 22;7(1):16072. doi: 10.1038/s41598-017-16405-2.
Mikhail S Dzyurkevich 1,  Denis A Babkov 2,  Nikita V Shtyrlin 1,  Olga Yu Mayka 2,  Alfiya G Iksanova 1,  Pavel M Vassiliev 2,  Konstantin V Balakin 1 3,  Alexander A Spasov 2,  Vadim V Tarasov 4,  George Barreto 5 6,  Yurii G Shtyrlin 1,  Gjumrakch Aliev 7 8 9
Affiliations

Affiliations

  • 1 Kazan (Volga region) Federal University, Kremlyovskaya 18, Kazan, 420008, Russia.
  • 2 Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd, 400131, Russia.
  • 3 I.M. Sechenov First Moscow State Medical University, Trubetskaya St. 8, bld 2, Moscow, 119991, Russia.
  • 4 Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia.
  • 5 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia.
  • 6 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.
  • 7 GALLY International Biomedical Research & Consulting LLC 7733 Louis Pasteur Dr. Suite #328, San Antonio, TX, 78229, USA. aliev03@gmail.com.
  • 8 School of Health Science and Healthcare Administration, University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA, 30097, USA. aliev03@gmail.com.
  • 9 Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia. aliev03@gmail.com.
PMID: 29167582 DOI: 10.1038/s41598-017-16405-2
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.

Figures
Products