☆ 4.5 Article

Discovery of a Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase with Oral Anti-Inflammatory Activity

ACS MEDICINAL CHEMISTRY LETTERS (2021)

期刊

ACS MEDICINAL CHEMISTRY LETTERS

卷 12, 期 5, 页码 782-790

出版社

AMER CHEMICAL SOC

DOI: 10.1021/acsmedchemlett.1c00044

关键词

Bruton's; BTK; atropisomer; covalent; K-inact

类别

Chemistry, Medicinal

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The discovery of a novel potent and selective covalent BTK inhibitor represents a promising approach to improving treatment outcomes in autoimmune disorders. Compound 27 shows selectivity for BTK, strong in vivo occupancy, sustained efficacy, and dose-dependent reduction of joint inflammation in a rat model of collagen-induced arthritis.

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

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