Novel N-substituted benzimidazolones as potent, selective, CNS-penetrant, and orally active M1 mAChR agonists

Brian Budzik, Vincenzo Garzya, Dongchuan Shi, Graham Walker, Marie Woolley-Roberts, Joanne Pardoe, Adam Lucas, Ben Tehan, Ralph A. Rivero, Christopher J. Langmead, Jeannette Watson, Zining Wu, Ian T. Forbes, Jian Jin

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.

Original languageEnglish
Pages (from-to)244-248
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume1
Issue number6
DOIs
StatePublished - 9 Sep 2010
Externally publishedYes

Keywords

  • 1-(N-substituted piperidin-4-yl)benzimidazolones
  • CNS-penetrant and orally active M mAChR agonists
  • M mAChR
  • M muscarinic acetylcholine receptor
  • benzimidazolones
  • subtype selective

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