title: Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists.
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.
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Brian
authors.initials: B
authors.lastname: Budzik
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Garzya
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Dongchuan
authors.initials: D
authors.lastname: Shi
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Graham
authors.initials: G
authors.lastname: Walker
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Marie
authors.initials: M
authors.lastname: Woolley-Roberts
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Joanne
authors.initials: J
authors.lastname: Pardoe
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Adam
authors.initials: A
authors.lastname: Lucas
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Ben
authors.initials: B
authors.lastname: Tehan
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Watson
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Zining
authors.initials: Z
authors.lastname: Wu
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Forbes
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
keywords: 1-(N-substituted piperidin-4-yl)benzimidazolones; CNS-penetrant and orally active M1 mAChR agonists; M1 mAChR; M1 muscarinic acetylcholine receptor; benzimidazolones; subtype selective