Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 530.1 Theories and mathematical physics
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 324-329 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260997
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Cancer; 4. Hdm2; 5. P53; 6. Protein?protein interaction

Tóm tắt

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23?ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.