Design of Selective PAK1 Inhibitor G-5555 [electronic resource] : Improving Properties by Employing an Unorthodox Low-p<em>K</em><sub>a</sub> Polar Moiety

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Ngôn ngữ: eng

Ký hiệu phân loại: 545 Quantitative analysis

Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015

Mô tả vật lý: Size: p. 1241-1246 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 261105

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pKa and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. Overall, these studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.
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