2,4,6-三氨基嘧啶作为一系列PI3Kδ选择性抑制剂中的新型铰链结合剂。
2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors.
作者信息
Patel Leena, Chandrasekhar Jayaraman, Evarts Jerry, Haran Aaron C, Ip Carmen, Kaplan Joshua A, Kim Musong, Koditek David, Lad Latesh, Lepist Eve-Irene, McGrath Mary E, Novikov Nikolai, Perreault Stephane, Puri Kamal D, Somoza John R, Steiner Bart H, Stevens Kirk L, Therrien Joseph, Treiberg Jennifer, Villaseñor Armando G, Yeung Arthur, Phillips Gary
机构信息
Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.
Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
出版信息
J Med Chem. 2016 Apr 14;59(7):3532-48. doi: 10.1021/acs.jmedchem.6b00213. Epub 2016 Mar 29.
Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.
抑制磷酸肌醇 3-激酶δ（PI3Kδ）是多种血液系统恶性肿瘤和炎症性疾病的一个有吸引力的靶点。在此，我们描述了一系列包含新型三氨基嘧啶铰链结合剂的螺旋桨状PI3Kδ抑制剂的发现和优化过程。采用电子和结构策略的组合来减轻醛氧化酶介导的代谢。这项药物化学研究最终确定了52，一种强效且高度选择性的PI3Kδ抑制剂，它在大鼠关节炎模型中显示出疗效。
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