Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI.
Basic Information
ID: ALA3804754
Journal: ACS Med Chem Lett
Title: Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI.
Authors: Pero JE, Rossi MA, Kelly MJ, Lehman HD, Layton ME, Garbaccio RM, O'Brien JA, Magliaro BC, Uslaner JM, Huszar SL, Fillgrove KL, Tang C, Kuo Y, Joyce LA, Sherer EC, Jacobson MA.
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.
CiteXplore: 26985321
DOI: 10.1021/acsmedchemlett.5b00459
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