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:	Tanya Michelle Jewell, Robert Steven Kania, Anand Sistla, Bennett Michael John, Michael R. Gehring, Evan Smith, Zehnder Luke Raymond, Shinji Yamazaki, Karen A. Maegley, Elena Z. Dovalsantos, Ben Burke, Fen Wang, Sacha Ninkovic, Jeff Wang, Joe Zhongxiang Zhou, Pei-Pei Kung, Min-Jean Yin, Michael J. Hickey, Martin James Wythes, Jerry Meng, Buwen Huang, Ping Kang, John F. Braganza, Ketan S. Gajiwala, Tatlock John H, Pramod P. Mehta
Rok vydání:	2011
Předmět:	Pyrimidine biology Chemistry Stereochemistry medicine.drug_class Carboxamide Metabolic stability Combinatorial chemistry Hsp90 Bioavailability chemistry.chemical_compound Heat shock protein Drug Discovery Alkoxy group biology.protein medicine Molecular Medicine Potency
Zdroj:	Journal of Medicinal Chemistry. 54:3368-3385
ISSN:	1520-4804 0022-2623
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
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::3fc866a72d07c6999eda9ddc940a1344 https://doi.org/10.1021/jm200128m Zobrazit plný text záznamu