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Identification of a new class of glucokinase activators through structure-based design.

Hinklin RJ, Boyd SA, Chicarelli MJ, Condroski KR, DeWolf WE, Lee PA, Lee W, Singh A, Thomas L, Voegtli WC, Williams L, Aicher TD
J Med Chem 56 7669-78 (2013)
Cited: 16 times
EuropePMC logo PMID: 24015910

Abstract

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.

Articles - 4mle mentioned but not cited (2)

  1. Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings. Mitchell MR, Tlusty T, Leibler S. Proc Natl Acad Sci U S A 113 E5847-E5855 (2016)
  2. Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase. D'Antonio EL, Deinema MS, Kearns SP, Frey TA, Tanghe S, Perry K, Roy TA, Gracz HS, Rodriguez A, D'Antonio J. Mol Biochem Parasitol 204 64-76 (2015)


Reviews citing this publication (3)

  1. Investigational insulin secretagogues for type 2 diabetes. Scheen AJ. Expert Opin Investig Drugs 25 405-422 (2016)
  2. Cyclobutanes in Small-Molecule Drug Candidates. van der Kolk MR, Janssen MACH, Rutjes FPJT, Blanco-Ania D. ChemMedChem 17 e202200020 (2022)
  3. A patent review of glucokinase activators and disruptors of the glucokinase--glucokinase regulatory protein interaction: 2011-2014. Filipski KJ, Pfefferkorn JA. Expert Opin Ther Pat 24 875-891 (2014)

Articles citing this publication (11)

  1. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study. Xu H, Sheng L, Chen W, Yuan F, Yang M, Li H, Li X, Choi J, Zhao G, Hu T, Li Y, Zhang Y, Chen L. Drug Des Devel Ther 10 1619-1626 (2016)
  2. The influence of intramolecular sulfur-lone pair interactions on small-molecule drug design and receptor binding. Hudson BM, Nguyen E, Tantillo DJ. Org Biomol Chem 14 3975-3980 (2016)
  3. C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators. Du X, Hinklin RJ, Xiong Y, Dransfield P, Park J, Kohn TJ, Pattaropong V, Lai S, Fu Z, Jiao X, Chow D, Jin L, Davda J, Veniant MM, Anderson DA, Baer BR, Bencsik JR, Boyd SA, Chicarelli MJ, Mohr PJ, Wang B, Condroski KR, DeWolf WE, Conn M, Tran T, Yang J, Aicher TD, Medina JC, Coward P, Houze JB. ACS Med Chem Lett 5 1284-1289 (2014)
  4. Structural insight into the glucokinase-ligands interactions. Molecular docking study. Ermakova E. Comput Biol Chem 64 281-296 (2016)
  5. 5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties. Kohn TJ, Du X, Lai S, Xiong Y, Komorowski R, Veniant M, Fu Z, Jiao X, Pattaropong V, Chow D, Cardozo M, Jin L, Conn M, DeWolf WE, Kraser CF, Hinklin RJ, Boys ML, Medina JC, Houze J, Dransfield P, Coward P. ACS Med Chem Lett 7 666-670 (2016)
  6. N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation. Grewal AS, Kharb R, Prasad DN, Dua JS, Lather V. Chem Biol Drug Des 93 364-372 (2019)
  7. Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394. Dransfield PJ, Pattaropong V, Lai S, Fu Z, Kohn TJ, Du X, Cheng A, Xiong Y, Komorowski R, Jin L, Conn M, Tien E, DeWolf WE, Hinklin RJ, Aicher TD, Kraser CF, Boyd SA, Voegtli WC, Condroski KR, Veniant-Ellison M, Medina JC, Houze J, Coward P. ACS Med Chem Lett 7 714-718 (2016)
  8. Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators. Grewal AS, Kharb R, Prasad DN, Dua JS, Lather V. BMC Chem 13 2 (2019)
  9. Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation. Wang Z, Shi X, Zhang H, Yu L, Cheng Y, Zhang H, Zhang H, Zhou J, Chen J, Shen X, Duan W. Eur J Med Chem 139 128-152 (2017)
  10. Structure based design, synthesis and biological evaluation of amino phosphonate derivatives as human glucokinase activators. Yellapu NK, Kilaru RB, Chamarthi N, Pvgk S, Matcha B. Comput Biol Chem 68 118-130 (2017)
  11. Organomediated cleavage of benzoyl group enables an efficient synthesis of 1-(6-nitropyridin-2-yl)thiourea and its application for developing 18F-labeled PET tracers. Wang J, Takahashi K, Shoup TM, Gong L, Li Y, El Fakhri G, Zhang Z, Brownell AL. Bioorg Chem 124 105804 (2022)


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