ABSTRACT
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
Subject(s)
Imidazoles/chemistry , Janus Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Cell Line , Janus Kinase 1/chemistry , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/chemistry , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Substrate SpecificityABSTRACT
A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Precursors/antagonists & inhibitors , Indoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Basophils/drug effects , Cell Degranulation/drug effects , Cell Line , Enzyme Inhibitors/pharmacology , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Oxyquinoline/chemistry , Oxyquinoline/pharmacology , Phosphorylation/drug effects , Rats , Solubility , Structure-Activity Relationship , Syk KinaseABSTRACT
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.