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ACS Med Chem Lett. 2016 Jan 10;7(3):312-7. doi: 10.1021/acsmedchemlett.5b00459. eCollection 2016 Mar 10.

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

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Departments of Medicinal Chemistry, In Vitro Sciences, Psychiatry Research, Central Pharmacology, Drug Metabolism, Process and Analytical Chemistry, and Structural Chemistry, Merck Research Laboratories , P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, United States.


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.


Schizophrenia; metabotropic glutamate receptor; positive allosteric modulator; time-dependent inhibition

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