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.
Subject(s)
Amides/chemical synthesis , Analgesics/chemical synthesis , Excitatory Amino Acid Antagonists/chemical synthesis , Pain/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Amides/administration & dosage , Amides/pharmacokinetics , Analgesics/administration & dosage , Analgesics/pharmacokinetics , Animals , Biological Availability , Brain/metabolism , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacokinetics , Humans , Pain/metabolism , Pain Measurement , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Stereoisomerism , Structure-Activity Relationship , Thiazoles/administration & dosage , Thiazoles/pharmacokineticsABSTRACT
The authors show by illustration that procedures used to validate the reliability of single-concentration high-throughput screens such as the signal window and Z' factor do not ensure sufficient reliability in potency estimates from concentration response assays. They develop the minimum significant ratio as a statistical parameter to characterize the fold change between 2 compounds run in the same experiment that can be considered a real difference and use this parameter to characterize the reliability of the assay. They adapt methods described by Bland and Altman to develop a simple set of 2 experiments to estimate the minimum significant ratio and show that this protocol can identify assays that lack reproducibility. The methods are then extended to validate the equivalency of the same assay run by multiple laboratories.
