Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia

Bioorg Med Chem Lett. 2013 Jan 1;23(1):346-50. doi: 10.1016/j.bmcl.2012.10.073. Epub 2012 Nov 1.

Abstract

Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / therapeutic use
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Cholinergic Agents / chemistry
  • Cholinergic Agents / pharmacokinetics
  • Cholinergic Agents / therapeutic use
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Protein Binding
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Rats
  • Receptor, Muscarinic M4 / chemistry
  • Receptor, Muscarinic M4 / metabolism*
  • Schizophrenia / drug therapy
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / pharmacokinetics
  • Thiophenes / therapeutic use

Substances

  • Amides
  • Cholinergic Agents
  • ML253
  • Pyridines
  • Receptor, Muscarinic M4
  • Thiophenes
  • pyridine