ABSTRACT
The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.
Subject(s)
Amides/chemistry , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Administration, Oral , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Autoimmune Diseases/drug therapy , Binding Sites , Binding, Competitive , Crystallography, X-Ray , Drug Evaluation, Preclinical , Half-Life , Humans , Interleukin-17/metabolism , Interleukin-23/pharmacology , Mice , Molecular Dynamics Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Protein Binding , Rats , Skin/drug effects , Skin/metabolism , Structure-Activity Relationship , Th17 Cells/cytology , Th17 Cells/drug effects , Th17 Cells/metabolismABSTRACT
The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.
Subject(s)
Antipruritics/chemistry , Drug Discovery , Pyridones/agonists , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Thiazoles/agonists , Animals , Antipruritics/pharmacology , CHO Cells , Cricetinae , Humans , Mice , Protein Binding/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively).
Subject(s)
Antipruritics/chemistry , Antipruritics/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Animals , Antipruritics/administration & dosage , CHO Cells , Cricetinae , Disease Models, Animal , Inhibitory Concentration 50 , Ligands , Mice , Mice, Inbred ICR , Molecular Structure , Protein Binding/drug effects , Pyridones/chemistryABSTRACT
Our lead compound 1 showed high affinity for both CB1 and CB2 receptors, suggesting the possibility of inducing psychoactive side effects through the CB1 receptor in the brain. To solve this issue, polar functional groups were introduced at the 3-position of the pyridone core of compound 1 to find CB1/2 dual agonists such as 17 and 20 which did not show any CNS side effects.
