Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4441-5. doi: 10.1016/j.bmcl.2009.05.051. Epub 2009 May 18.

Abstract

The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Glucocorticoids / chemistry
  • Glucuronic Acid / chemistry
  • Immediate-Early Proteins / antagonists & inhibitors*
  • Immediate-Early Proteins / chemistry
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Conformation
  • Protein Kinase Inhibitors / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Glucocorticoids
  • Immediate-Early Proteins
  • Protein Kinase Inhibitors
  • Glucuronic Acid
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase