459133-66-5Relevant articles and documents
Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
Scott, Jack D.,DeMong, Duane E.,Greshock, Thomas J.,Basu, Kallol,Dai, Xing,Harris, Joel,Hruza, Alan,Li, Sarah W.,Lin, Sue-Ing,Liu, Hong,Macala, Megan K.,Hu, Zhiyong,Mei, Hong,Zhang, Honglu,Walsh, Paul,Poirier, Marc,Shi, Zhi-Cai,Xiao, Li,Agnihotri, Gautam,Baptista, Marco A. S.,Columbus, John,Fell, Matthew J.,Hyde, Lynn A.,Kuvelkar, Reshma,Lin, Yinghui,Mirescu, Christian,Morrow, John A.,Yin, Zhizhang,Zhang, Xiaoping,Zhou, Xiaoping,Chang, Ronald K.,Embrey, Mark W.,Sanders, John M.,Tiscia, Heather E.,Drolet, Robert E.,Kern, Jonathan T.,Sur, Sylvie M.,Renger, John J.,Bilodeau, Mark T.,Kennedy, Matthew E.,Parker, Eric M.,Stamford, Andrew W.,Nargund, Ravi,McCauley, John A.,Miller, Michael W.
, p. 2983 - 2992 (2017)
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Design, synthesis, and Structure–Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors
Chan, Shingpan,Ding, Ke,Duan, Yunxin,Tu, Zheng-Chao,Wang, Jie,Zhang, Zhang,Zhu, Sihua
, (2020/07/21)
Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure–Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 μM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.
Disulfide-Catalyzed Iodination of Electron-Rich Aromatic Compounds
Iida, Keisuke,Ishida, Shunsuke,Watanabe, Takamichi,Arai, Takayoshi
, (2019/06/13)
Herein, a disulfide-catalyzed electrophilic iodination of aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH) has been developed. The disulfide activates DIH as a Lewis base to promote the iodination reaction in acetonitrile under mild conditions. This system is applicable to a wide range of electron-rich aromatic compounds, including acetanilide, anisole, imidazole, and pyrazole derivatives.
