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J Med Chem. 2015 Jul 23;58(14):5437-44. doi: 10.1021/acs.jmedchem.5b00734. Epub 2015 Jul 2.

Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.

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1
Takeda California, 10410 Science Center Drive, San Diego, California 92121, United States.

Abstract

The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.

PMID:
26087137
DOI:
10.1021/acs.jmedchem.5b00734
[Indexed for MEDLINE]

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