Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI
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- 作者：Joseph E. Pero ; Michael A. Rossi ; Michael J. Kelly III ; Hannah D. G. F. Lehman ; Mark E. Layton ; Robert M. Garbaccio ; Julie A. O’Brien ; Brian C. Magliaro ; Jason M. Uslaner ; Sarah L. Huszar ; Kerry L. Fillgrove ; Cuyue Tang ; Yuhsin Kuo ; Leo A. Joyce ; Edward C. Sherer ; Marlene A. Jacobson
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：7
- 期：3
- 页码：312-317
- 全文大小：413K
- ISSN：1948-5875
文摘
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.