Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase

被引：111

作者：

Angst, Daniela ^{[1
]}

Gessier, Francois ^{[1
]}

Janser, Philipp ^{[1
]}

Vulpetti, Anna ^{[1
]}

Walchli, Rudolf ^{[1
]}

Beerli, Christian ^{[2
]}

Littlewood-Evans, Amanda ^{[2
]}

Dawson, Janet ^{[2
]}

Nuesslein-Hildesheim, Barbara ^{[2
]}

Wieczorek, Grazyna ^{[2
]}

Gutmann, Sascha ^{[3
]}

Scheufler, Clemens ^{[3
]}

Hinniger, Alexandra ^{[3
]}

Zimmerlin, Alfred ^{[4
]}

Funhoff, Enrico G. ^{[5
]}

Pulz, Robert ^{[1
]}

Cenni, Bruno ^{[2
]}

机构：

[1] Novartis Inst BioMed Res, Global Discovery Chem, CH-4002 Basel, Switzerland

[2] Novartis Inst BioMed Res, Autoimmun Transplantat & Inflammat, CH-4002 Basel, Switzerland

[3] Novartis Inst BioMed Res, Chem Biol & Therapeut, CH-4002 Basel, Switzerland

[4] Novartis Inst BioMed Res, PK Sci, CH-4002 Basel, Switzerland

[5] Novartis Inst BioMed Res, Preclin Safety, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 10期

关键词：

COLLAGEN-INDUCED ARTHRITIS; B-CELL DEVELOPMENT; TEC FAMILY; FOLLOW-UP; BTK; IBRUTINIB; ACTIVATION; MICE; AUTOIMMUNITY; RECEPTOR;

D O I：

10.1021/acs.jmedchem.9b01916

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.

引用

页码：5102 / 5118

页数：17

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