Discovery of potent and selective PKC-θ inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 1, 2007, Pages 225-230

  Cywin, Charles L ^a   Dahmann, Georg ^b   Prokopowicz III, Anthony S ^a   Young, Erick R R ^a   Magolda, Ronald L ^a   Cardozo, Mario G ^a   Cogan, Derek A ^a   DiSalvo, Darren ^a   Ginn, John D ^a   Kashem, Mohammed A ^a   Wolak, John P ^a   Homon, Carol A ^a   Farrell, Thomas M ^a   Grbic, Heather ^a   Hu, Hanbo ^a   Kaplita, Paul V ^a   Liu, Lisa H ^a   Spero, Denice M ^a   Jeanfavre, Deborah D ^a   O'Shea, Kathy M ^a   White, Della M ^a   Woska Jr , Joseph R ^a   Brown, Maryanne L ^a   more..

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

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

Author keywords

Hit to lead; Inhibitor; Kinase; PKC

Indexed keywords

ALKYL GROUP; DIAMINE DERIVATIVE; NITRO DERIVATIVE; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; PROTEIN KINASE C INHIBITOR; PROTEIN KINASE C THETA; PROTEIN KINASE C THETA INHIBITOR; PYRIMIDINE DERIVATIVE;

ANIMAL CELL; ARTICLE; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYDROGEN BOND; IC 50; NONHUMAN; STEREOSPECIFICITY; STRUCTURE ACTIVITY RELATION;

CD4-POSITIVE T-LYMPHOCYTES; HUMANS; INTERLEUKIN-2; ISOENZYMES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN CONFORMATION; PROTEIN KINASE C; PROTEIN KINASE INHIBITORS; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33845671162     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.09.056     Document Type: Article

References (16)

1. Baier G., Telford D., Giampa L., Coggeshall K.M., Baier-Bitterlich G., Isakov N., and Altman A. J. Biol. Chem. 268 (1993) 4997
2. Sun Z., Arendt C.W., Ellmeier W., Schaeffer E.M., Sunshine M.J., Gandhi L., Annes J., Petrilka D., Kupfer A., Schwartzberg P.L., and Littman D.R. Nature 404 (2000) 402
3. Monks C.R.F., Freiberg B.A., Kupfer H., Sciaky N., and Kupfer A. Nature 395 (1998) 82
4. Monks C.R.F., Kupfer H., Tamir I., Barlow A., and Kupfer A. Nature 385 (1997) 83
5. ® from Spotfire, Inc., 212 Elm St., Somerville, MA, 02144 USA.
6. For recent patents on pyrimidines as kinase inhibitors: Dahmann, G. US Patent Application US 2003/171359; Chem. Abstr. 2003, 319721.
7. Cardozo, M. G. U.S. Patent Applications U.S. 2005/124640 and U.S. 2004/242613; Chem. Abstr. 2005, 497492.
8. Baudler, M. U.S. Patent Application U.S. 2005/0222186; Chem. Abstr. 2003, 1006977.
9. For recent patent on indolinones as kinase inhibitors: Roth, G. J. U.S. Patent Application U.S. 2005/043389; Chem. Abstr. 2004, 80649.
10. Takahashi T., Naito T., and Inoue S. Chem. Pharm. Bull. 6 (1958) 334
11. 4OH in MeOH). Compound 24, 43 mg, 89% was isolated as a yellow solid; MS(M+H) = 449 mp 96-100.
12. Cherry M., and Williams D.H. Curr. Med. Chem. 11 (2004) 663
13. 2, 0.01% Chaps, 200 μM TCEP (Pierce # 77720), 100 μM Na orthovanadate, and Protease Inhibitor Cocktail (Boehringer Mannheim 1836153; 1 tablet to 50 mL buffer)) is pre-incubated with compound dilutions at rt for 10 min. The reaction is started with a mixture of peptide substrate (RFARKGSLRQKNV, Panvera P2760) and ATP (final assay concentrations are 1 μM peptide and 10 μM ATP). The assay plates are incubated for 60 min at rt. In the FP detection step, fluorescein-labeled phosphopeptide tracer and anti-phosphoserine antibody diluted in quench buffer are added to reaction mixture and incubated for 90 min at rt. FP is measured on a LJL Analyst using fluorescein filters (485 nm excitation, 530 nm emission, 505 nm dichroic).
14. 50 = 0.63 μM at 100 μM ATP.
15. Inhibition of IL-2 production was determined by isolating human CD4+ T cells from whole blood by positive selection. Purified T cells are activated through the TCR and CD28 via anti-CD3 and anti-CD28 mAbs. Compounds are diluted in 5% DMSO to a final concentration of 0.125% DMSO at every dose. 50,000 cells are added in 100 μL of media/well followed by 100 μL of compound or DMSO alone. Cells are incubated overnight at 37 °C and then the supernatants are analyzed for IL-2 with the R&D Systems IL-2 ELISA kit (Cat#02050) following a 1:10 dilution.
16. Kaplita P.V., Hu H., Liu L., Farrell T.M., Grbic H., and Spero D.M. JALA 10 (2005) 140