Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M(4) muscarinic acetylcholine receptor agonists

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2909-12. doi: 10.1016/j.bmcl.2014.04.083. Epub 2014 May 9.

Abstract

We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po).

Keywords: M(4) muscarinic acetylcholine receptor; Muscarinic acetylcholine receptor agonist; N-Sulfonyl-7-azaindoline; Schizophrenia; Subtype-selective agonist.

MeSH terms

  • Administration, Oral
  • Animals
  • Behavior, Animal / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Methamphetamine / antagonists & inhibitors
  • Methamphetamine / pharmacology
  • Molecular Structure
  • Motor Activity / drug effects
  • Piperidines / administration & dosage
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Receptor, Muscarinic M4 / agonists*
  • Structure-Activity Relationship
  • Sulfonamides / administration & dosage
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Piperidines
  • Receptor, Muscarinic M4
  • Sulfonamides
  • Methamphetamine