ABSTRACT
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Isoquinolines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase , Crystallography, X-Ray , Drug Design , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolismABSTRACT
The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclopropanes/chemical synthesis , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrroles/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Caco-2 Cells , Crystallography, X-Ray , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Gene Knockdown Techniques , High-Throughput Screening Assays , Humans , Interleukin-2/physiology , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , Janus Kinase 3/genetics , Janus Kinase 3/metabolism , Mice , Models, Molecular , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , RNA, Small Interfering/genetics , Rats , Receptors, Interleukin-6/physiology , Signal Transduction/drug effects , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Subject(s)
Drug Design , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , RatsABSTRACT
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
