|
|||||
|
|
3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: hit to lead studies |
|
| Authors: | Gilbert Adam M Bursavich Matthew G Lombardi Sabrina Adedoyin Adedayo Dwyer Jason M Hughes Zoe Kern Jeffrey C Khawaja Xavier Rosenzweig-Lipson Sharon Moore William J Neal Sarah J Olsen Michael Rizzo Stacey J Sukoff Springer Dane |
| Affiliation: | Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA |
| Abstract: | A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC50: 926 nM), potent mGluR5 NAMs showing excellent potencies (IC50s <50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (Ki: 21 nM) and antagonism (IC50: 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk). |
| Keywords: | mGluR5 Negative allosteric modulator Anxiolytic LipE |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |