Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quino

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• 作者：Felix Gonzalez-Lopez de Turiso ; Xiaolin Hao ; Youngsook Shin ; Minna Bui ; Iain D. G. Campuzano ; Mario Cardozo ; Michelle C. Dunn ; Jason Duquette ; Benjamin Fisher ; Robert S. Foti ; Kirk Henne ; Xiao He ; Yi-Ling Hu ; Ron C. Kelly ; Michael G. Johnson ; Brian S. Lucas ; John McCarter ; Lawrence R. McGee ; Julio C. Medina ; Daniela Metz ; Tisha San Miguel ; Deanna Mohn ; Thuy Tran ; Christine Vissinga ; Sharon Wannberg ; Douglas A. Whittington ; John Whoriskey ; Gang Yu ; Leeanne Zalameda ; Xuxia Zhang ; Timothy D. Cushing
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：59
• 期：15
• 页码：7252-7267
• 全文大小：905K
• 年卷期：0
• ISSN：1520-4804

文摘

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.