ABSTRACT
A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.
ABSTRACT
The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.
Subject(s)
Histamine Agonists/chemistry , Histamine Agonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, Histamine H3/metabolism , Animals , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/pharmacology , Caco-2 Cells , Histamine Agonists/pharmacokinetics , Humans , Male , Piperidines/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Trans-Activators/metabolism , Transcriptional Regulator ERGSubject(s)
Antidepressive Agents/pharmacology , Cognition/drug effects , Receptors, Histamine H3/metabolism , Thiazoles/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Drug Design , Humans , Male , Mice , Mice, Inbred C57BL , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistrySubject(s)
Benzene/chemistry , Histamine Antagonists/chemistry , Oxazoles/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3/chemistry , Animals , Caco-2 Cells , Cell Line , Cognition Disorders/drug therapy , Drug Inverse Agonism , Humans , Male , Mice , Microsomes, Liver/metabolism , Oxazoles/pharmacokinetics , Pyrrolidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
Subject(s)
Histamine H3 Antagonists/pharmacology , Oxazoles/pharmacology , Receptors, Histamine H3/chemistry , Animals , CHO Cells , Caco-2 Cells , Cell Line , Cricetinae , Cricetulus , Drug Design , Drug Inverse Agonism , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/chemistry , Humans , Imidazoles/chemistry , Mice , Oxazoles/chemical synthesis , Oxazoles/chemistry , Prefrontal Cortex/drug effects , Rats , Rats, Wistar , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
SAR around 4,6-diaminopyrimidine derivatives allowed the discovery of the first potent dual M(3) antagonists and PDE4 inhibitors. Various chemical modulations around that scaffold led to the discovery of ucb-101333-3 which is characterized by the most interesting profile on both targets.
