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

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.