Abstract
Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.
MeSH terms
-
Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
-
Animals
-
Antitubercular Agents / chemical synthesis
-
Antitubercular Agents / pharmacology
-
Arthritis, Experimental / chemically induced
-
Arthritis, Experimental / microbiology
-
Arthritis, Experimental / prevention & control*
-
Arthritis, Rheumatoid / microbiology
-
Arthritis, Rheumatoid / prevention & control
-
Drug Design*
-
Male
-
Mice
-
Mice, Inbred DBA
-
Molecular Structure
-
Mycobacterium tuberculosis / drug effects*
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / pharmacology*
-
Tuberculosis / complications
-
Tuberculosis / microbiology
Substances
-
Antitubercular Agents
-
Protein Kinase Inhibitors
-
Agammaglobulinaemia Tyrosine Kinase