Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia

https://doi.org/10.1016/j.bmcl.2013.10.057Get rights and content

Abstract

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.

References and notes (33)

  • K. Crawford

    Crit. Care Nurs. Clin. North Am.

    (2013)
  • F. Farrokhi et al.

    Best Pract. Res. Clin. Endocrinol. Metab.

    (2011)
  • K.M. Dungan et al.

    Lancet

    (2009)
  • F.M. Matschinsky

    Trends Pharmacol. Sci.

    (2013)
  • WHO. 2013, Diabetes Fact Sheet,...
  • J.P. Boyle et al.

    Diabetes Care

    (1936)
  • E.S. Huang et al.

    Diabetes Care

    (2009)
  • CDC. 2012, Diagnosed Diabetes Grows at a Dramatic Rate Throughout the United States,...
  • A. Pichardo-Lowden et al.

    Curr. Diabetes Rep.

    (2012)
  • M. Rendell et al.

    Expert Rev. Endocrinol. Metab.

    (2013)
  • N.J. Wei et al.

    Curr. Diabetes Rep.

    (2012)
  • C. van Noord et al.

    Neth. J. Med.

    (2012)
  • G.E. Umpierrez et al.

    J. Clin. Endocrinol. Metab.

    (2012)
  • H. Talley Michele et al.

    J. Am. Acad. Nurse Pract.

    (2012)
  • A. Qureshi et al.

    Hosp. Pract.

    (2012)
  • A.M. Deane et al.

    Diabetes

    Obes. Metab.

    (2013)
  • Cited by (10)

    • Hetero-substituted sulfonamido-benzamide hybrids as glucokinase activators: Design, synthesis, molecular docking and in-silico ADME evaluation

      2020, Journal of Molecular Structure
      Citation 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 Chemistry
      Citation 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].

    • Non-systemic Intestine-Targeted Drugs

      2016, Progress in Medicinal Chemistry
      Citation 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.

    View all citing articles on Scopus
    View full text