title: Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain.
abstract: High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). 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.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, MS 2545, Kenilworth, NJ 07033-0539, USA. Stephanie.Brumfield@merck.com
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brumfield
authors.forename: Peter
authors.initials: P
authors.lastname: Korakas
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Silverman
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: Julius J
authors.initials: JJ
authors.lastname: Matasi
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.forename: Chad E
authors.initials: CE
authors.lastname: Bennett
authors.forename: Duane A
authors.initials: DA
authors.lastname: Burnett
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Chad E
authors.initials: CE
authors.lastname: Knutson
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Wu
authors.forename: T K
authors.initials: TK
authors.lastname: Sasikumar
authors.forename: Martin
authors.initials: M
authors.lastname: Domalski
authors.forename: Rosalia
authors.initials: R
authors.lastname: Bertorelli
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Grilli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lozza
authors.forename: Angelo
authors.initials: A
authors.lastname: Reggiani
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy; D004195:Disease Models, Animal; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D011744:Pyrimidinones; D018094:Receptors, Metabotropic Glutamate; D013876:Thiophenes; C104077:metabotropic glutamate receptor type 1