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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.

SUBMITTER: Budzik B 

PROVIDER: S-EPMC4007837 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists.

Budzik Brian B   Garzya Vincenzo V   Shi Dongchuan D   Walker Graham G   Woolley-Roberts Marie M   Pardoe Joanne J   Lucas Adam A   Tehan Ben B   Rivero Ralph A RA   Langmead Christopher J CJ   Watson Jeannette J   Wu Zining Z   Forbes Ian T IT   Jin Jian J  

ACS medicinal chemistry letters 20100608 6


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 select  ...[more]

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