ABSTRACT
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Autoimmune Diseases/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Immunity/drug effects , Janus Kinase 2/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM).
Subject(s)
Obesity/drug therapy , Piperidines/pharmacology , Piperidines/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Receptors, Somatostatin/antagonists & inhibitors , Binding, Competitive/drug effects , Drug Evaluation, Preclinical , Humans , Molecular Structure , Piperidines/chemistry , Pyrrolidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
