148900-69-0Relevant articles and documents
Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2
Shan, Hengyue,Liu, Jianping,Shen, Jiali,Dai, Jialin,Xu, Gang,Lu, Kuankuan,Han, Chao,Wang, Yaru,Xu, Xiaolong,Tong, Yilun,Xiang, Huaijiang,Ai, Zhiyuan,Zhuang, Guanglei,Hu, Junhao,Zhang, Zheng,Li, Ying,Pan, Lifeng,Tan, Li
, p. 855 - 9,865 (2021/05/18)
The COVID-19 pandemic has been disastrous to society and effective drugs are urgently needed. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention. In this work, we describe the development of a potent and selective SCoV2 PLpro inhibitor, 19. The inhibitor not only effectively blocks substrate cleavage and immunosuppressive function imparted by PLpro, but also markedly mitigates SCoV2 replication in human cells, with a submicromolar IC50. We further present a convenient and sensitive activity probe, 7, and complementary assays to readily evaluate SCoV2 PLpro inhibitors in vitro or in cells. In addition, we disclose the co-crystal structure of SCoV2 PLpro in complex with a prototype inhibitor, which illuminates their detailed binding mode. Overall, these findings provide promising leads and important tools for drug discovery aiming to target SCoV2 PLpro.
Discovery of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-diones and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4
Tsou,Liu, Xiaoxiang,Birnberg, Gary,Kaplan, Joshua,Otteng, Mercy,Tran, Tritin,Kutterer, Kristina,Tang, Zhilian,Suayan, Ron,Zask, Arie,Ravi, Malini,Bretz, Angela,Grillo, Mary,Mcginnis, John P.,Rabindran, Sridhar K.,Ayral-Kaloustian, Semiramis,Mansour, Tarek S.
experimental part, p. 2289 - 2310 (2010/02/28)
The series of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-dione and 4-[(pyridylmethyl)aminometh-ylene]isoquinoline-1,3-(2H,4H)-dione derivatives reported here represents a novel class of potential antitumor agents, which potently and selectively inhibit CDK4 over CDK2 and CDK1. In the benzylamino headpiece, a 3-OH substituent is required on the phenyl ring for CDK4 inhibitory activity, which is further enhanced when an iodo, aryl, heteroaryl, t-butyl, or cyclopentyl substituent is introduced at the C-6 position of the isoquinoline-1,3-dione core. To circumvent the metabolic liability associated with the phenolic OH group on the 4-substituted 3-OH phenyl headpiece, we take two approaches: first, introduce a nitrogen o- or p- to the 3-OH group in the phenyl ring; second, replace the phenyl headpiece with N-substituted 2-pyridones. We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
Substituted alkylamine derivatives and methods of use
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, (2008/06/13)
Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.