Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors
| Autor: | Jing Wang, Zhulin Zhang, Tadimeti S. Rao, Jun Yu, Xiong Li, Tianhai Yuan, Wei-Guo Su, Qing Wang, Zheng Zhang, Yu Cai, Hong Jia, Scott D. Bembenek, Jennifer Venable, James P. Edwards, Yang Sai, Fuying Shi, Jianyang Weng, Wei Chen, Ping Ren, Guangxiu Dai, Kun Xiao |
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| Rok vydání: | 2019 |
| Předmět: |
Class I Phosphatidylinositol 3-Kinases
01 natural sciences Molecular Docking Simulation Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice Drug Discovery Moiety Animals Class Ib Phosphatidylinositol 3-Kinase Humans Rats Wistar Quinazolinone 030304 developmental biology Phosphoinositide-3 Kinase Inhibitors 0303 health sciences Chemistry Dual inhibitor Highly selective Combinatorial chemistry Arthritis Experimental 0104 chemical sciences Sprague dawley Isoenzymes 010404 medicinal & biomolecular chemistry RAW 264.7 Cells PC-3 Cells Molecular Medicine Female Hinge region Drug metabolism |
| Zdroj: | Journal of medicinal chemistry. 62(10) |
| ISSN: | 1520-4804 |
| Popis: | An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species. |
| Databáze: | OpenAIRE |
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