Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia
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Hetero-substituted sulfonamido-benzamide hybrids as glucokinase activators: Design, synthesis, molecular docking and in-silico ADME evaluation
2020, Journal of Molecular StructureCitation Excerpt :GK facilitates phosphorylation of glucose to glucose-6-phosphate and is expressed in cells of the liver, pancreas, gut, and brain of humans and many other vertebrates [3–6]. Glucokinase activators (GKA) not only lowers blood glucose concentrations by enhancing glucose uptake in the liver but also increases insulin secretion from pancreatic beta cells which makes it a promising molecular target for antidiabetic therapy [7–11]. Acquisition of the facts of GK enzyme and other parameters, several small molecules were designed and explored targeting GK to activate the allosteric site of protein.
Structural attributes influencing unbound tissue distribution
2020, European Journal of Medicinal ChemistryCitation Excerpt :Liver also has a large number of transporters [48] known to transport drug-like molecules (e.g., Oatps, Oats, Octs, Ntcp) and receptors (e.g., ASGPR) at the sinusoidal membrane to enhance uptake of structurally diverse compounds. Compound 56, for example, is a known OATP substrate [16] and the liver to plasma Kpuu is 13, consistent with being an uptake transporter substrate. Brain, on the hand, is a highly regulated and protected organ with tight cellular junctions and high efflux activities from P-gp and Bcrp at the blood-brain barrier to maintain homeostasis of the brain microenvironment [7].
Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus
2017, Bioorganic and Medicinal Chemistry LettersNon-systemic Intestine-Targeted Drugs
2016, Progress in Medicinal ChemistryCitation Excerpt :The risk of collecting unwanted “baggage” is also lowered, examples of which include the propensity to cause drug–drug interactions stemming from inhibition of hepatic cytochrome P450 (CYP) enzymes [4,5], or cardiotoxicity manifested as a result of, for example, inhibition of the hERG potassium channel [6]. Recently, there have been many reports of single-compartment [7], tissue-targeted [8] drugs aimed at treating maladies in the liver [9–11], bone [12] and kidney [11,13] following systemic administration. However, the simplest, and arguably the most effective, approach to non-systemic [14] drug discovery involves topical methodologies, wherein the drug is administered directly to a surface of the body.
A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes
2022, Chemical Biology and Drug DesignGlucokinase activation as antidiabetic therapy: effect of nutraceuticals and phytochemicals on glucokinase gene expression and enzymatic activity
2021, Archives of Physiology and Biochemistry