Article ; Online: Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.
Bioorganic & medicinal chemistry letters
2020 Volume 30, Issue 17, Page(s) 127390
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 ... ...
| 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. |
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| MeSH term(s) | Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; 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/chemistry ; Imidazoles/metabolism ; Imidazoles/therapeutic use ; Molecular Dynamics Simulation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/therapeutic use ; Pyrazines/chemistry ; Pyrazines/metabolism ; Pyrazines/therapeutic use ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; src-Family Kinases/antagonists & inhibitors ; src-Family Kinases/metabolism |
| Chemical Substances | Bridged Bicyclo Compounds ; Imidazoles ; Protein Kinase Inhibitors ; Pyrazines ; imidazo(1,5-a)pyrazine ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) |
| Language | English |
| Publishing date | 2020-07-11 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 1063195-1 |
| ISSN | 1464-3405 ; 0960-894X |
| ISSN (online) | 1464-3405 |
| ISSN | 0960-894X |
| DOI | 10.1016/j.bmcl.2020.127390 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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