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    • GK also called hexokinase IV or D is

    2021-11-24

    GK, also called hexokinase IV or D, is a glycolytic enzyme that converts APETx2 mg to glucose-6-phosphate. GK has unique characteristics compared with those of the ubiquitously expressed hexokinase isoforms I–III, and is predominantly expressed in the pancreas and liver. In pancreatic β-cells, GK regulates the threshold for GSIS. In hepatocytes, GK regulates glycogen synthesis and hepatic glucose production, and its activity is controlled by glucokinase regulatory protein (GKRP) [[7], [8], [9]]. Considering that the activation of GK in the pancreas and liver could lead to increased insulin secretion from pancreatic β-cells and glucose uptake in the liver, allosteric activators of GK (GKAs) have emerged as attractive targets for the treatment of T2DM [10]. Following the initial discovery of RO0281675 [11,12], several GKAs, including phenyl acetamides, benzamides, and imidazolylacetamides, have been reported (Fig. 1) [[13], [14], [15], [16], [17], [18]]. To date, several GKAs have advanced to clinical studies and have demonstrated an ability to lower blood glucose levels in both healthy subjects and patients with T2DM. However, in these clinical studies hypoglycemia, increased plasma triglycerides (TG), and loss of efficacy within several months, were determined to be the main obstacles to developing GKAs as therapeutic agents for T2DM [16,19]. It is believed that hypoglycemia is caused by the overstimulation of islet β-cell GK, while increased plasma TG is the result of overstimulation of liver GK. However, the cause of the loss of efficacy in the short term remains to be elucidated [20]. To mitigate these limitations, various types of GKAs have been discovered and have progressed to human clinical trials [18]. Although most were terminated at Phase I or Phase II, some GKAs (including vTv Therapeutics's TTP399 and Hua Medicine's HMS5552) remain currently active and have shown positive results in recent clinical trials [[21], [21](a), [21](b), [21](c), [21](d), [21](e), [21](f), [22](a), [22](b), [22], [23]]. These two compounds exhibit characteristics that are unique among GKAs. TTP399 is a liver-selective GKA that does not affect the inhibition of GK by GKRP in the liver. The manufacturer suggests that disruption of the GK-GKRP interaction leads to hypoglycemia and dyslipidemia. HMS5552 has an amino acid-based structure, which is markedly different from that of other GKAs. The development of GKA as a clinical agent for the treatment of T2DM therefore requires the identification of a new type of GKA with characteristics different from those of other GKAs. Herein, we report the discovery of a new type of hepatoselective GKA with a unique structure, robust GK activation potency, and benign safety profile. In addition, a favorable distribution pattern in the pancreas and liver was observed. To the best of our knowledge, an orally active GKA exhibiting such characteristics has not been disclosed to date. In a previous report, the discovery of novel small molecule 7, using molecular modeling-aided medicinal chemistry approaches, was described [24]. This compound has a characteristic structure with an amide portion connecting the phenyl thiophene ring and cyclopentathiazole. GKAs with this type of structure are poorly represented in the literature. Therefore, compound 7 was selected as the lead compound for our discovery series.
    Results and discussion
    Conclusions To identify an orally active, structurally unique GKA, conversion of the phenyl group of water-insoluble compound 7 led to the discovery of the pyrrolidinyl-thiophene derivative 38. This compound had favorable solubility and in vivo efficacy in a mouse model for OGTT. Unfortunately, 38 had a high binding affinity to hERG potassium channels. The optimization of 38 using a zwitterion approach led to the discovery of novel GKA 59. This compound produced a significant reduction in blood glucose levels in normal and diabetic mice, and had a benign safety profile in toxicological studies. Due to favorable in vivo properties and low pancreatic distribution, 59 exhibited a low risk of hypoglycemia as well as properties unique among other reported GKAs. These results prompted us to select 59 as our clinical candidate.