Remibrutinib (LOU-064) is a potent, highly selective and orally bioavailable covalent inhibitor of bruton tyrosine kinase (BTK) with an IC50 of 0.023μM. It has the potential for Chronic urticaria (CU) treatment. 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. 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.

Physicochemical Properties

Molecular Formula	C27H27F2N5O3
Molecular Weight	507.531792879105
Exact Mass	507.208
CAS #	1787294-07-8
PubChem CID	118107483
Appearance	White to off-white solid powder
LogP	3.9
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	9
Heavy Atom Count	37
Complexity	815
Defined Atom Stereocenter Count	0
SMILES	FC1=C(C(NC2C=C(C=C(C3C(=C(N)N=CN=3)OCCN(C(C=C)=O)C)C=2C)F)=O)C=CC(=C1)C1CC1
InChi Key	CUABMPOJOBCXJI-UHFFFAOYSA-N
InChi Code	InChI=1S/C27H27F2N5O3/c1-4-23(35)34(3)9-10-37-25-24(31-14-32-26(25)30)20-12-18(28)13-22(15(20)2)33-27(36)19-8-7-17(11-21(19)29)16-5-6-16/h4,7-8,11-14,16H,1,5-6,9-10H2,2-3H3,(H,33,36)(H2,30,31,32)
Chemical Name	N-(3-{6-amino-5-[2-(N-methylprop-2-enamido)ethoxy]pyrimidin-4-yl}-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide
Synonyms	LOU064 LOU-064 LOU 064
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	Remibrutinib (Example 6) inhibited Btk enzyme activity in the biochemical enzyme assay, with an IC50 value of 1 nM [1]. Remibrutinib reduced blood Btk enzyme activity in an in vitro B cell activation test, with an IC50 value of 0.023 μM. Sector Lewis was put under anesthesia, and whole blood was extracted from the abdominal aorta [1].
References	[1]. Novel amino pyrimidine derivatives. Patent WO2015079417A1. [2]. New treatments for chronic urticaria. Ann Allergy Asthma Immunol. 2019 Aug 23.
Additional Infomation	Drug Indication Treatment of multiple sclerosis Treatment of chronic spontaneous urticaria

Solubility Data

Solubility (In Vitro)

DMSO : ~125 mg/mL (~246.29 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.10 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.10 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9703 mL	9.8516 mL	19.7033 mL
	5 mM	0.3941 mL	1.9703 mL	3.9407 mL
	10 mM	0.1970 mL	0.9852 mL	1.9703 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.