Abstract：
:V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Niculescu-Duvaz D,Niculescu-Duvaz I,Suijkerbuijk BM,Ménard D,Zambon A,Nourry A,Davies L,Manne HA,Friedlos F,Ogilvie L,Hedley D,Takle AK,Wilson DM,Pons JF,Coulter T,Kirk R,Cantarino N,Whittaker S,Marais R,Springer CJdoi
10.1016/j.bmc.2010.06.031subject
Has Abstractpub_date
2010-09-15 00:00:00pages
6934-52issue
18eissn
0968-0896issn
1464-3391pii
S0968-0896(10)00559-6journal_volume
18pub_type
杂志文章abstract：:4-Aminoantipyrine (4-amino-1,5-dimethyl-2-phenylpyrazole-3-one) and its analogues have been found to be compounds of interest for their anti-inflammatory, analgesic, antiviral, antipyretic, antirheumatic and antimicrobial activities. In the present study, Schiff base analogues of 4-aminoantipyrine were synthesized by ...
journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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更新日期：2013-06-01 00:00:00
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journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2004.11.017
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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doi：10.1016/j.bmc.2007.03.084
更新日期：2007-06-15 00:00:00
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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更新日期：2009-09-01 00:00:00
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更新日期：2009-12-01 00:00:00
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更新日期：2017-08-01 00:00:00
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journal_title：Bioorganic & medicinal chemistry
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更新日期：2016-03-01 00:00:00
abstract：:Phenylacetate induced tumor cytostasis and differentiation. The chemotherapeutic function of the compound in lung cancer has been previously reported, however, whether or not phenylacetate performs other activities is not known. In this study, the potential usage of synthetic phenylacetate derivatives, 4-fluoro-N-buty...
journal_title：Bioorganic & medicinal chemistry
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doi：10.1016/j.bmc.2008.11.028
更新日期：2009-01-01 00:00:00
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journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
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更新日期：2010-06-01 00:00:00
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journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
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更新日期：2009-09-15 00:00:00
abstract：:The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective an...
journal_title：Bioorganic & medicinal chemistry
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更新日期：2014-06-15 00:00:00
