Preclinical evaluation of a new glucokinase activator, YH10561 as a therapeutic drug candidate for type II diabetes mellitus : 제 2형 당뇨병 치료제 후보물질인 포도당인산화 효소 활성제 YH10561의 전임상 평가

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수의과대학 수의학과
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서울대학교 대학원
glucokinaseglucokinase activatortype 2 diabetes mellitusoral glucose tolerance testpreclinical drug developmentliverpancreas
학위논문 (박사)-- 서울대학교 대학원 : 수의학과 수의생리학전공, 2016. 8. 류판동.
Glucokinase (GK) is a subtype of hexokinase isozyme that phosphorylates glucose to glucose-6-phosphate. Glucokinase activators are currently being investigated as potential diabetes therapeutics due to their effects on the inhibition of hepatic glucose production and insulin secretion. In this study, I evaluated the aniti-diabetic efficacy, pharmacokinetics, and preclinical safety of YH10561, a novel glucokinase activator synthesized by Yuhan Research Institute. YH10561 increased the glucokinase activity with a high potency (IC50 = 72.1 ~ 85.0 nM), but was completely inactive against hexokinase I and hexokinase II (test up to 1 μM). In vitro, YH10561 concentration dependently activated glucose-dependent glucokinase activity and promoted insulin secretion. In the in vivo animal models, the YH10561 treatment (5 ~ 150 mg/kg) significantly improved glucose homeostasis in oral glucose tolerance test (OGTT) of normal, diet induced obese (DIO) and ob/ob mice. To investigate the pharmacokinetic characteristics of YH10561, pharmacokinetics and tissue distribution of YH10561 are assessed in various experimental animals and its in vitro metabolism and drug interaction potential are studied. YH10561 exhibited a high oral bioavailability with the value of 84% in rats and over 100% in mice and dogs. In mice, rat and dogs, the values of apparent terminal half-life is 2.6, 0.51 ± 0.06 and 3.7 ± 0.4 hours, respectively. In mice, linear pharmacokinetics was observed between oral doses of 5 to 150 mg/kg and saturation of clearance was not observed. The volume of distribution was low in mice and rats (0.33-0.35 L/kg) and intermediate in dogs (0.92 L/kg). In vitro, YH10561 was not highly protein-bound (80%–91%). In mouse, rat and dog liver microsomes, YH10561 was relatively stable and did not inhibit major drug metabolizing enzymes at a high concentration (up to 25 μM). Based on the available in vitro and animal data, it can be concluded that YH10561 has favorable pharmacokinetic properties to develop as a clinical candidate. To evaluate the possible clinical adverse event, genotoxicity and the in vivo rat toxicity study were conducted. YH10561 was not genotoxic in the Ames test or micronucleus assays. In the in vivo rat toxicity study, YH10561 was administered for single dose to 4 weeks. Major toxicological findings include focal erosion in the stomach, increased weight of the liver and decreased weight of the testis with histological changes. To confirm that toxicological changes in the testis are related to GKA pharmacology, histological changes in the testis of other glucokinase activators and YH10561 were compared. While PSN-GK1 showed similar changes in the testis, GKA-50 did not. These data indicate that testicular toxicity of YH10561 is chemical-specific and is not caused by its glucokinase activating mechanism.

Taken together, these results demonstrate that YH10561 is a potent and effective compound for type 2 diabetes mellitus therapy with favorable oral pharmacokinetic characteristics. However, YH10561 has some toxicological limitations in terms of developing as a clinical candidate. These limitations are likely to be overcame if one finds other GKA back-up compounds without such toxicities.
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Theses (Ph.D. / Sc.D._수의학과)
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