compound 9 [PMID: 26006010]   

GtoPdb Ligand ID: 9761

Compound class: Synthetic organic
Comment: Compound 9 [PMID: 26006010] is a reversible BTK inhibitor that was designed to have a long target residency time with a resulting increase in the duration of in vivo target engagement, and with the overall aim of improving in vivo drug efficacy [1]. Compound 9 has a cysteine-reactive, inverted cyanoacrylamide scaffold structure that interacts with Cys481, a residue that lies outwith the catalytic domain of the enzyme but close to the ATP pocket (and is also a target of the irreversible inhibitor ibrutinib). It has good aqueous solubility and is orally bioavailable. Compound 9 may be PRN473 as described in [3], but PRN473's structure has not been formally disclosed.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 9
Hydrogen bond donors 1
Rotatable bonds 10
Topological polar surface area 135.42
Molecular weight 610.28
XLogP 4.03
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES N#CC(=CC(N(C1COC1)C)(C)C)C(=O)N1CCCC1Cn1nc(c2c1ncnc2N)c1ccc(cc1F)Oc1ccccc1
Isomeric SMILES N#C/C(=C\C(N(C1COC1)C)(C)C)/C(=O)N1CCC[C@H]1Cn1nc(c2c1ncnc2N)c1ccc(cc1F)Oc1ccccc1
InChI InChI=1S/C33H35FN8O3/c1-33(2,40(3)23-18-44-19-23)15-21(16-35)32(43)41-13-7-8-22(41)17-42-31-28(30(36)37-20-38-31)29(39-42)26-12-11-25(14-27(26)34)45-24-9-5-4-6-10-24/h4-6,9-12,14-15,20,22-23H,7-8,13,17-19H2,1-3H3,(H2,36,37,38)/b21-15+/t22-/m0/s1
InChI Key YELZMARZEBVKBL-VAZXNAHHSA-N
References
1. Bradshaw JM, McFarland JM, Paavilainen VO, Bisconte A, Tam D, Phan VT, Romanov S, Finkle D, Shu J, Patel V et al.. (2015)
Prolonged and tunable residence time using reversible covalent kinase inhibitors.
Nat. Chem. Biol., 11 (7): 525-31. [PMID:26006010]
2. Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE et al.. (2011)
Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis.
Nat. Chem. Biol., 7 (1): 41-50. [PMID:21113169]
3. Herter JM, Margraf A, Volmering S, Correia BE, Bradshaw JM, Bisconte A, Hill RJ, Langrish CL, Lowell CA, Zarbock A. (2018)
PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen-1 signalling.
Br. J. Pharmacol., 175 (3): 429-439. [PMID:29130484]
4. Xu D, Kim Y, Postelnek J, Vu MD, Hu DQ, Liao C, Bradshaw M, Hsu J, Zhang J, Pashine A et al.. (2012)
RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents.
J. Pharmacol. Exp. Ther., 341 (1): 90-103. [PMID:22228807]