Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3822-5. doi: 10.1016/j.bmcl.2016.04.083. Epub 2016 Apr 29.

Abstract

This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.

Keywords: CNS penetration; M(1); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Structure–activity relationship (SAR).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Central Nervous System / drug effects*
  • Central Nervous System Agents / chemical synthesis
  • Central Nervous System Agents / chemistry
  • Central Nervous System Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rats
  • Receptor, Muscarinic M1 / metabolism*
  • Structure-Activity Relationship

Substances

  • Central Nervous System Agents
  • Heterocyclic Compounds
  • Pyridines
  • Pyrroles
  • Receptor, Muscarinic M1
  • VU0453595