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

Autor: Pero JE; 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., Rossi MA; 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., Kelly MJ 3rd; 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., Lehman HD; 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., Layton ME; 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., Garbaccio RM; 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., O'Brien JA; 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., Magliaro BC; 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., Uslaner JM; 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., Huszar SL; 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., Fillgrove KL; 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., Tang C; 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., Kuo Y; 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., Joyce LA; 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., Sherer EC; 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., Jacobson MA; 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.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Jan 10; Vol. 7 (3), pp. 312-7. Date of Electronic Publication: 2016 Jan 10 (Print Publication: 2016).
DOI: 10.1021/acsmedchemlett.5b00459
Abstrakt: 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.
Databáze: MEDLINE