吡咯并[2,1-f][1,2,4]三嗪-4-胺作为强效和选择性PI3Kδ抑制剂的发现与构效关系研究
Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors.
作者信息
Bhide Rajeev S, Neels James, Qin Lan-Ying, Ruan Zheming, Stachura Sylwia, Weigelt Carolyn, Sack John S, Stefanski Kevin, Gu Xiaomei, Xie Jenny H, Goldstine Christine B, Skala Stacey, Pedicord Donna L, Ruepp Stefan, Dhar T G Murali, Carter Percy H, Salter-Cid Luisa M, Poss Michael A, Davies Paul
机构信息
Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
出版信息
Bioorg Med Chem Lett. 2016 Sep 1;26(17):4256-60. doi: 10.1016/j.bmcl.2016.07.047. Epub 2016 Jul 21.
Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
I类磷脂酰肌醇-3-激酶（PI3K）信号异常是导致许多免疫紊乱和癌症的关键因素。我们已确定4-氨基吡咯并三嗪为一种新型化学类型，它能选择性抑制PI3Kδ信号，尽管其不与PI3Kδ亚型的特异性口袋结合。构效关系（SAR）研究促使我们鉴定出化合物30，该化合物在小鼠血蓝蛋白（KLH）和胶原诱导的关节炎（CIA）模型中显示出疗效。
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