BTK inhibitor 16 [PMID: 30122225]   Click here for help

GtoPdb Ligand ID: 10076

Synonyms: example 90 [US20160264548]
Compound class: Synthetic organic
Comment: This compound is reported as an irreversible, covalent inhibitor of Bruton's tyrosine kinase (BTK) [2]. It is compound 23 (example 90) as claimed in Merck's patent US20160264548A1 [1].
Because of its expression pattern on B cells, macrophages, neutrophils, and monocytes (NOT T cells) and its essential role in B lymphocyte development and function, BTK continues to be investigated as a valid therapeutic target for the treatment of diseases that involve B-cell and/or macrophage activation (e.g. B-cell malignancies, asthma and rheumatoid arthritis). Ibrutinib was the first-in-class small molecule BTK inhibitor to reach the clinic. Unfortunately, ibrutinib causes severe adverse effects that are in the main, attributed to its off-target profile. As a result, second-generation BTK inhibitors with optimised structures and improved selectivity are being developed. Inhibitor 16 described here, exhibits comparable cellular potency to ibrutinib but has a higher kinome selectivity against undesirable off-targets.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 97.99
Molecular weight 456.18
XLogP 4.35
No. Lipinski's rules broken 0
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Canonical SMILES C=CC(=O)N1CC2CC1CN2c1ccc(c(n1)Oc1ccc(cc1)Oc1ccccc1)C(=O)N
Isomeric SMILES C=CC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(c(n1)Oc1ccc(cc1)Oc1ccccc1)C(=O)N
InChI InChI=1S/C26H24N4O4/c1-2-24(31)30-16-17-14-18(30)15-29(17)23-13-12-22(25(27)32)26(28-23)34-21-10-8-20(9-11-21)33-19-6-4-3-5-7-19/h2-13,17-18H,1,14-16H2,(H2,27,32)/t17-,18-/m0/s1
1. Qiu H, Caldwell RD, Neagu C, Mochalkin I, Liu-Bujalski L, Jones R, Tate D, Johnson TL, Gardberg A. (2016)
Heteroaryl compounds as btk inhibitors and uses thereof.
Patent number: US20160264548A1. Assignee: Merck Patent GmbH. Priority date: 21/10/2013. Publication date: 15/09/2016.
2. Qiu H, Liu-Bujalski L, Caldwell RD, Follis AV, Gardberg A, Goutopoulos A, Grenningloh R, Head J, Johnson T, Jones R et al.. (2018)
Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit.
Bioorg Med Chem Lett, 28 (17): 2939-2944. [PMID:30122225]