Indazolylpyrazolopyrimidine as highly potent B-Raf inhibitors with in vivo activity

Journal of Medicinal Chemistry

Volumn 53, Issue 21, 2010, Pages 7874-7878

  Wang, Xiaolun ^a   Berger, Dan M ^a   Salaski, Edward J ^a   Torres, Nancy ^a   Dutia, Minu ^a   Hanna, Cilien ^a   Hu, Yongbo ^a   Levin, Jeremy I ^a   Powell, Dennis ^a   Wojciechowicz, Donald ^a   Collins, Karen ^a   Frommer, Eileen ^a   Lucas, Judy ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 [2,6 DIFLUORO 4 (5 METHYL 2,5 DIAZABICYCLO (2 2 1) HEPTAN 2 YL) PHENYL] 3 (1H INDAZOL 4 YL) 2 (PYRIDIN 4 YL) PYRAZOLO [1,5 R] PYRIMIDINE; B RAF KINASE INHIBITOR; INDAZOLYLPYRAZOLO [1,5 A] PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CANCER INHIBITION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; MOUSE; NONHUMAN; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; BICYCLO COMPOUNDS, HETEROCYCLIC; CELL LINE, TUMOR; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; INDAZOLES; MICE; MODELS, MOLECULAR; MUTATION; NEOPLASM TRANSPLANTATION; PROTO-ONCOGENE PROTEINS B-RAF; PYRAZOLES; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS;

EID: 78149247725     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm1007566     Document Type: Article

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7. A model (active conformation) built from 2FB8 (PDB) (3a) was used.
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9. 50 = 0.28 nM in their assay. See Supporting Information for details.
10. SS = 4.7 L/kg.
11. Another efficacy study with Colo205 model also showed great tumor growth inhibition. See Supporting Information for details.
12. Data are not shown and will be present elsewhere.
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16. Compound 8l is inefficacious in tumor cell lines with wild type B-Raf.