Discovery of N-substituted 7-azaindoline derivatives as potent, orally available M1 and M4 muscarinic acetylcholine receptors selective agonists

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3189-93. doi: 10.1016/j.bmcl.2014.04.085. Epub 2014 May 10.

Abstract

We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M1 and M4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M1 and M4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.

Keywords: 7-Azaindoline derivative; Antipsychotic agents; M(1) muscarinic acetylcholine receptor; M(4) muscarinic acetylcholine receptor; Schizophrenia; Subtype-selective agonist.

MeSH terms

  • Administration, Oral
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Haplorhini
  • Humans
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Piperidines / administration & dosage
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Receptor, Muscarinic M1 / agonists*
  • Receptor, Muscarinic M4 / agonists*
  • Structure-Activity Relationship

Substances

  • Indoles
  • Piperidines
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M4