| Literature DB >> 26985321 |
Joseph E Pero1, Michael A Rossi1, Michael J Kelly1, Hannah D G F Lehman1, Mark E Layton1, Robert M Garbaccio1, Julie A O'Brien1, Brian C Magliaro1, Jason M Uslaner1, Sarah L Huszar1, Kerry L Fillgrove1, Cuyue Tang1, Yuhsin Kuo1, Leo A Joyce1, Edward C Sherer1, Marlene A Jacobson1.
Abstract
Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.Entities:
Keywords: Schizophrenia; metabotropic glutamate receptor; positive allosteric modulator; time-dependent inhibition
Year: 2016 PMID： 26985321 PMCID： PMC4789683 DOI： 10.1021/acsmedchemlett.5b00459
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345