An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1958-1963. doi: 10.1016/j.bmcl.2018.03.034. Epub 2018 Apr 5.

Abstract

Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4 t limited ghrelin-induced food intake.

Keywords: CAMKK2; Inhibitor; Satiety.

MeSH terms

  • Administration, Oral
  • Animals
  • Brain / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
  • Eating / drug effects
  • Ghrelin / pharmacology
  • Hydrogen Bonding
  • Indoles / chemistry
  • Indoles / metabolism
  • Inhibitory Concentration 50
  • Mice
  • Mutagenesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism

Substances

  • Ghrelin
  • Indoles
  • Protein Kinase Inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase