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Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers
- Source :
- Journal of Medicinal Chemistry. 59:9173-9200
- Publication Year :
- 2016
- Publisher :
- American Chemical Society (ACS), 2016.
-
Abstract
- Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fce receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure–activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties an...
- Subjects :
- 0301 basic medicine
Atropisomer
biology
010405 organic chemistry
medicine.drug_class
Kinase
Chemistry
Stereochemistry
B-cell receptor
Carboxamide
01 natural sciences
0104 chemical sciences
03 medical and health sciences
030104 developmental biology
immune system diseases
hemic and lymphatic diseases
Drug Discovery
medicine
biology.protein
Molecular Medicine
Structure–activity relationship
Bruton's tyrosine kinase
Transferase
Tyrosine kinase
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........7b451ee92e76fc192317aad794597941