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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
-
Administration, Oral
-
Amides / administration & dosage
-
Amides / chemical synthesis*
-
Amides / pharmacokinetics
-
Analgesics / administration & dosage
-
Analgesics / chemical synthesis*
-
Analgesics / pharmacokinetics
-
Animals
-
Biological Availability
-
Brain / metabolism
-
Excitatory Amino Acid Antagonists / administration & dosage
-
Excitatory Amino Acid Antagonists / chemical synthesis*
-
Excitatory Amino Acid Antagonists / pharmacokinetics
-
Humans
-
Pain / drug therapy*
-
Pain / metabolism
-
Pain Measurement
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
-
Receptors, Metabotropic Glutamate / metabolism
-
Stereoisomerism
-
Structure-Activity Relationship
-
Thiazoles / administration & dosage
-
Thiazoles / chemical synthesis*
-
Thiazoles / pharmacokinetics
Substances
-
Amides
-
Analgesics
-
Excitatory Amino Acid Antagonists
-
Receptors, Metabotropic Glutamate
-
Thiazoles
-
metabotropic glutamate receptor type 1