Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide
| Autor: | Luke, Zehnder, Michael, Bennett, Jerry, Meng, Buwen, Huang, Sacha, Ninkovic, Fen, Wang, John, Braganza, John, Tatlock, Tanya, Jewell, Joe Zhongxiang, Zhou, Ben, Burke, Jeff, Wang, Karen, Maegley, Pramod P, Mehta, Min-Jean, Yin, Ketan S, Gajiwala, Michael J, Hickey, Shinji, Yamazaki, Evan, Smith, Ping, Kang, Anand, Sistla, Elena, Dovalsantos, Michael R, Gehring, Robert, Kania, Martin, Wythes, Pei-Pei, Kung |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Models Molecular Cell Membrane Permeability Transplantation Heterologous Administration Oral Biological Availability Mice Nude Antineoplastic Agents In Vitro Techniques Binding Competitive Mice Structure-Activity Relationship Drug Stability Cell Line Tumor Animals Humans HSP90 Heat-Shock Proteins Melanoma Blood Proteins Rats Pyrimidines Microsomes Liver Pyrazoles Female Drug Screening Assays Antitumor Hydrophobic and Hydrophilic Interactions Neoplasm Transplantation Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 54(9) |
| ISSN: | 1520-4804 |
| Popis: | A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles. |
| Databáze: | OpenAIRE |
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