High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Duane Burnett合作论文数Arkuda Therapeutics8
Chad Knutson合作论文数6Peter Korakas合作论文数4Wu Wen-Lian合作论文数4Deen B. Tulshian合作论文数4Brian A McKittrick合作论文数3Elizabeth M. Smith合作论文数3
Joel Harris合作论文数Department of Chemistry, University of Utah3Eugenia Y Kiselgof合作论文数3Martin Domalski合作论文数2hyunjin kim合作论文数2Cheng Li合作论文数2Li Qiang合作论文数2Troy M. Mccracken合作论文数2Gianluca Lozza合作论文数2
William J. Greenlee合作论文数MedChem Discovery Consulting, LLC;Harrington Discovery Institute, University Hospitals Case Medical Center2Rosalia Bertorelli合作论文数2Mariagrazia Grilli合作论文数Schering-Plough Research Institute2
Thavalakulamgara K Sasikumar合作论文数Department of Medicinal Chemistry, Merck Research Laboratories2
Angelo Reggiani合作论文数Schering-Plough Research Institute2Thomas Bara合作论文数2henry m vaccaro合作论文数1Hongmei Li合作论文数1Mary Ann Caplen合作论文数1Robert D Mazzola合作论文数1
John P Caldwell合作论文数1Ls Silverman合作论文数1Alessio Veltri合作论文数1Mary Cohen-Williams合作论文数1Julie Lee合作论文数1Palani Anandan合作论文数1Chu Inhou合作论文数1Vicarel Monica合作论文数1Brumfield Stephanie合作论文数1Xuanjia Peng合作论文数1Gilbert Eric J合作论文数1Zhiqiang Zhao合作论文数1Lixin Song合作论文数Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory1Lili Zhang合作论文数1John Clader合作论文数Chaparral Veterinary Center, PC1David Cole合作论文数Department of Philosophy, University of Minnesota-Duluth1Dong Xiao合作论文数1Silva Fredduzzi合作论文数1Andrew W Stamford合作论文数1Mark D. Mcbriar合作论文数1Jared N. Cumming合作论文数1Hubert Josein合作论文数1Julius J. Matasi合作论文数1
Tin-Yau Chan合作论文数Transcell Technologies, Inc.1
