title: 3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity.
abstract: The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46258, USA. fisher_matthew_j@lilly.com
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Backer
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.forename: Kim E
authors.initials: KE
authors.lastname: Garbison
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gruber
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.forename: Smriti
authors.initials: S
authors.lastname: Iyengar
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.forename: Anne
authors.initials: A
authors.lastname: Kingston
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.forename: Linglin
authors.initials: L
authors.lastname: Li
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: Steven C
authors.initials: SC
authors.lastname: Peters
authors.forename: Lee
authors.initials: L
authors.lastname: Phebus
authors.forename: Rosa Maria A
authors.initials: RM
authors.lastname: Simmons
authors.forename: Ellen
authors.initials: E
authors.lastname: van der Aar
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D000577:Amides; D000700:Analgesics; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1