Huang Xianhai, Zhou Wei, Liu Xiaoxiang, Li Hongmei, Sun George, Mandal Mihirbaran, Vicarel Monica, Zhu Xiaohong, Bennett Chad, McCraken Troy, Pissarnitski Dmitri, Zhao Zhiqiang, Cole David, Gallo Gioconda, Zhu Zhaoning, Palani Anandan, Aslanian Robert, Clader John, Czarniecki Michael, Greenlee William, Burnett Duane, Cohen-Williams Mary, Hyde Lynn, Song Lixin, Zhang Lili, Chu Inhou, Buevich Alexei
Department of Medicinal Chemistry, Department of In Vitro Biology, Department of In Vivo Biology, Drug Metabolism, and Structual Elucidation, Merck Research Laboratory , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
ACS Med Chem Lett. 2012 Sep 4;3(11):931-5. doi: 10.1021/ml300209g. eCollection 2012 Nov 8.
Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.
基于恶二唑啉γ-分泌酶调节剂（GSMs）的结构框架，发现稠合恶二嗪（3）是具有选择性且口服生物可利用的γ-分泌酶调节剂（GSMs）。尽管在结构上相关，但最初的修饰表明，构效关系（SARs）并不能从恶二唑啉系列转化到恶二嗪系列。随后对稠合恶二嗪核心的C3和C4位置进行修饰的SAR研究，有助于鉴定出如化合物8r和8s等GSMs，它们在许多动物模型中具有高效的体外和体内活性，且具有非常理想的物理和药理性质。通过制备稠合吗啉恶二嗪实现了体外活性和选择性的进一步提高。如在化合物8s的动物研究中观察到的，APP切割特异性的改变而非整体γ-分泌酶活性的降低，以及底物积累和Notch加工过程中没有变化，证实了恶二嗪系列化合物是有效的GSMs。
