Optimisation of ITK inhibitors through successive iterative design cycles

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 6, 2011, Pages 1852-1856

  Herdemann, Matthias ^a,b   Weber, Alexander ^a,c   Jonveaux, Jérôme ^a,d   Schwoebel, Frank ^a   Stoeck, Michael ^a   Heit, Isabelle ^a  

^a Nycomed GmbH   (Germany)

^b EPO   (Netherlands)

^c BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^d NOXXON PHARMA AG   (Germany)

Author keywords

Anti CD3 IL 2 mouse model; In vivo testing; Interleukin 2 inducible T cell kinase; Lead optimisation

Indexed keywords

AMIDE; INDAZOLE DERIVATIVE; INTERLEUKIN 2; INTERLEUKIN 2 INDUCIBLE T LYMPHOCYTE KINASE; INTERLEUKIN 2 INDUCIBLE T LYMPHOCYTE KINASE INHIBITOR; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; SULFONAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL ASSAY; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOKINE RELEASE; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG STRUCTURE; DRUG TOLERABILITY; ENZYME ASSAY; ENZYME INHIBITION; FEMALE; IN VIVO STUDY; INHIBITION KINETICS; MOUSE; NONHUMAN;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES;

EID: 79952363246     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.035     Document Type: Article

References (18)

1. N. Yamada, Y. Kawakami, H. Kimura, H. Fukamachi, G. Baier, A. Altman, T. Kato, Y. Inagaki, and T. Kawakami Biochem. Biophys. Res. Commun. 192 1993 231
2. J.D. Siliciano, T.A. Morrow, and S.V. Desiderio Proc. Natl. Acad. Sci. U.S.A. 89 1992 11194
3. S.D. Heyeck, H.M. Wilcox, S.C. Bunnell, and L.J. Berg J. Biol. Chem. 272 1997 25401
4. K.Q. Liu, S.C. Bunnell, C.B. Gurniak, and L.J. Berg J. Exp. Med. 187 1998 1721
5. E.M. Schaeffer, J. Debnath, G. Yap, D. McVicar, X.C. Liao, D.R. Littman, A. Sher, H.E. Varmus, M.J. Lenardo, and P.L. Schwartzberg Science 284 1999 638
6. D.J. Fowell, K. Shinkai, X.C. Liao, A.M. Beebe, R.L. Coffman, D.R. Littman, and R.M. Locksley Immunity 11 1999 399
7. A.T. Miller, H.M. Wilcox, Z. Lai, and L.J. Berg Immunity 21 2004 67
8. C. Mueller, and A. August J. Immunol. 170 2003 5056
9. T.A. Lin, K.W. McIntyre, J. Das, C. Liu, K.D. O'Day, B. Penhallow, C.Y. Hung, G.S. Whitney, D.J. Shuster, X. Yang, R. Townsend, J. Postelnek, S.H. Spergel, J. Lin, R.V. Moquin, J.A. Furch, A.V. Kamath, H. Zhang, P.H. Marathe, J.J. Perez-Villar, A. Doweyko, L. Killar, J.H. Dodd, J.C. Barrish, J. Wityak, and S.B. Kanner Biochemistry 43 2004 11056
10. M. Herdemann, I. Heit, F.-U. Bosch, G. Quintini, C. Scheipers, and A. Weber Bioorg. Med. Chem. Lett. 20 2010 6998
11. K. Brown, J.M. Long, S.C. Vial, N. Dedi, N.J. Dunster, S.B. Renwick, A.J. Tanner, J.D. Frantz, M.A. Fleming, and G.M. Cheetham J. Biol. Chem. 279 2004 18727
12. P.R. Gerber, and K.M.A.B. Muller J. Comput. Aided Mol. Des. 9 1995 251
13. www.moloc.ch.
14. A.F. Abdel-Magid, C.A. Maryanoff, and K.G. Carson Tetrahedron Lett. 31 1990 5595
15. A.F. Abdel-Magid, and C.A. Maryanoff Synlett 111 1990 537
16. 4. Removal of the solvent under reduced pressure gave the desired crude product. Purification of 11o was performed by flash chromatgraphy. After a first chromatography on basic silica gel with DCM/MeOH (95:5) the product (purity 90%) was submitted to a second flash chromatography with cyclohexane/AcOEt/MeOH (60:20:20) as eluent to provide 216 mg (23% overall yield) of pure 11o.
17. Anti-CD3 IL-2 mouse model: Female BALB/c mice (∼20 g body weight) received either one of the three doses of 11o (1, 3, 10 mg/kg body weight) intravenously 10 min or orally (10 mg/kg) 1 h before intravenous injection of a monoclonal anti-CD3 stimulating antibody (10 μg/kg body weight, BD PharMingen, clone: 145-2C11, Cat. No.01080D). The positive control group received vehicle (saline) intravenously and the antibody at the same dose for an equivalent length of time. Two hours after stimulation mice were finally anaesthetized and blood samples were taken by heart puncture. Suppression of antibody induced stimulation was described by the determination of IL-2 levels in plasma samples. Cytokine concentrations were measured by ELISA (R&D Systems, Quantikine mouse IL-2 ELISA Kit, Cat. No. M2000).
18. Supplementary data.