Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI

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 effici...

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Published in:ACS medicinal chemistry letters 2016-03, Vol.7 (3), p.312-317
Main Authors: Pero, Joseph E, Rossi, Michael A, Kelly, Michael J, Lehman, Hannah D. G. F, Layton, Mark E, Garbaccio, Robert M, O’Brien, Julie A, Magliaro, Brian C, Uslaner, Jason M, Huszar, Sarah L, Fillgrove, Kerry L, Tang, Cuyue, Kuo, Yuhsin, Joyce, Leo A, Sherer, Edward C, Jacobson, Marlene A
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Language:English
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00459