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Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.

St Jean DJ, Ashton KS, Bartberger MD, Chen J, Chmait S, Cupples R, Galbreath E, Helmering J, Hong FT, Jordan SR, Liu L, Kunz RK, Michelsen K, Nishimura N, Pennington LD, Poon SF, Reid D, Sivits G, Stec MM, Tadesse S, Tamayo N, Van G, Yang KC, Zhang J, Norman MH, Fotsch C, Lloyd DJ, Hale C
J Med Chem 57 325-38 (2014)
Cited: 6 times
EuropePMC logo PMID: 24405213

Abstract

In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

Reviews citing this publication (4)

  1. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Raimondo A, Rees MG, Gloyn AL. Curr Opin Lipidol 26 88-95 (2015)
  2. Molecular targeting of the GK-GKRP pathway in diabetes. Hale C, Lloyd DJ, Pellacani A, Véniant MM. Expert Opin Ther Targets 19 129-139 (2015)
  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)
  4. Recent Updates on Glucokinase Activators and Glucokinase Regulatory Protein Disrupters for the Treatment of Type 2 Diabetes Mellitus. Kaushik A, Kaushik M. Curr Diabetes Rev 15 205-212 (2019)

Articles citing this publication (2)

  1. Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus. Xu J, Lin S, Myers RW, Trujillo ME, Pachanski MJ, Malkani S, Chen HS, Chen Z, Campbell B, Eiermann GJ, Elowe N, Farrer BT, Feng W, Fu Q, Kats-Kagan R, Kavana M, McMasters DR, Mitra K, Tong X, Xu L, Zhang F, Zhang R, Addona GH, Berger JP, Zhang B, Parmee ER. Bioorg Med Chem Lett 27 2063-2068 (2017)
  2. Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface. Martinez JA, Xiao Q, Zakarian A, Miller BG. Biochemistry 56 3150-3157 (2017)


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