Discovery and optimization of thieno[2,3-d]pyrimidines as B-Raf inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 1, 2012, Pages 747-752

  Packard, Garrick K ^a   Papa, Patrick ^a   Riggs, Jennifer R ^a   Erdman, Paul ^a   Tehrani, Lida ^a   Robinson, Dale ^a   Harris, Roy ^a   Shevlin, Graziella ^a   Perrin Ninkovic, Sophie ^a   Hilgraf, Robert ^a   McCarrick, Margaret A ^a   Tran, Tam ^a   Fleming, Yuedi ^a   Bai, April ^a   Richardson, Samantha ^a   Katz, Jason ^a   Tang, Yang ^a   Leisten, Jim ^a   Moghaddam, Mehran ^a   Cathers, Brian ^a   Zhu, Dan ^a   Sakata, Steven ^a   more..

^a CELGENE CORPORATION   (United States)

Author keywords

B Raf inhibitor; PDE4 inhibitor; Thieno 2,3 d pyrimidine

Indexed keywords

B RAF KINASE INHIBITOR; SCAFFOLD PROTEIN; THIENO[2,3 D]PYRIMIDINE DERIVATIVE;

ARTICLE; IC 50; MEDICAL RESEARCH; NONHUMAN; SCREENING; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; MAP KINASE SIGNALING SYSTEM; MODELS, CHEMICAL; PROTEIN ISOFORMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS B-RAF; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 84655175052     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.03.006     Document Type: Article

References (11)

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5. For experimental details of compound synthesis and in vitro assays please see: McKenna, J.; Papa, P. W.; Sakata, S. T.; Erdman, P. E.; Packard, G. K. WO 2007/084560.
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7. 6 cells/mL (final cell density = 233,000 cells/well) and a final compound concentration of 3 μM. Percentage of parent disappearance was determined after 60 min of incubation at 37 °C by removing two aliquots (one at time zero and one at 60 min) and quenching the reaction with three volumes of 100% cold acetonitrile. Samples were mixed on a multi-tube vortexer for one minute and a volume of the mixture was filtered through a Captiva (Varian) 0.45 μm pore size polypropylene filter plate. Sample extracts were analyzed by LC-MS/MS to determine parent compound levels, reported as % remaining (mean ± SD).
8. iv = 116 mL/min/kg.
9. (0-infinity) was the area under the plasma drug concentration curve from time zero to time infinity following the iv dosing.
10. Initial molecular modeling coordinates of B-Raf came from the RCSB published crystal structure complex 1UWH containing wild-type B-Raf and sorafenib: Wan, P. T.; Garnett, M. J.; Roe, S. M.; Lee, S.; Niculescu-Duvaz, D.; Good, V. M.; Jones, C. M. Marshall, C. J.; Springer, C. J.; Barford, D.; Marais, R. Cell 2004, 116, 855. Protein chain A was used for modeling. All molecular modeling was performed using MOE software: Molecular Operating Environment (MOE), version 2001.01; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada H3A 2R7, 2005. Compounds were docked into the protein coordinates from 1UWH so that the carboxamide functionality formed hydrogen bonds to the hinge residue CYS 531. The inhibitor and all B-Raf residues within 6 of the inhibitor were allowed to minimize using the MMFF94× force field and a distance-dependent dielectric constant, while the rest of the protein was held fixed.
11. For a representative procedure see: C.A. Pratilas, B.S. Taylor, Q. Ye, A. Viale, C. Sander, D.B. Solit, and N. Rosen Proc. Natl. Acad. Sci. 11 2009 4519