ABSTRACT
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Arthritis, Experimental/drug therapy , Binding Sites , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Half-Life , Humans , Imidazoles/metabolism , Imidazoles/therapeutic use , Molecular Dynamics Simulation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Pyrazines/metabolism , Pyrazines/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolismABSTRACT
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Drug Discovery , Imidazoles/pharmacology , Morpholines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Arthritis, Rheumatoid/metabolism , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Models, Molecular , Molecular Structure , Morpholines/chemical synthesis , Morpholines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolismABSTRACT
We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.
Subject(s)
Carboxylic Acids/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase , Animals , Humans , RatsABSTRACT
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.
