ABSTRACT
In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.
Subject(s)
Antirheumatic Agents/chemistry , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/therapeutic use , Pyrroles/chemistry , Pyrroles/therapeutic use , Agammaglobulinaemia Tyrosine Kinase , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/enzymology , Humans , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
SAR studies were performed on a series of 2-arylamido-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide derivatives as cannabinoid receptor agonists. Starting from a HTS hit both potency and selectivity could be improved. Modifications to the thiophene fusion and C-3 amides were studied. A representative compound 3t produced analgesia when dosed orally in inflammatory pain models of writhing and carrageenan-induced allodynia.
