Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint

J Med Chem. 2015 Dec 24;58(24):9663-79. doi: 10.1021/acs.jmedchem.5b01367. Epub 2015 Dec 1.

Abstract

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 μM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Cell Nucleus / metabolism
  • Crystallography, X-Ray
  • Cytoplasm / metabolism
  • Glucokinase / metabolism*
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology
  • Thiophenes / chemistry*
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology

Substances

  • Adaptor Proteins, Signal Transducing
  • Blood Glucose
  • GCKR protein, human
  • Hypoglycemic Agents
  • N-((2-amino-5-chloro-3-fluoro-4-pyridinyl)(7-(4-(1-hydroxy-1-methylethyl)-2-pyridinyl)-1-benzothiophen-2-yl)methyl)cyclopropanesulfonamide
  • Sulfonamides
  • Thiophenes
  • Glucokinase