945756-13-8Relevant articles and documents
SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors
Forsyth, Timothy,Kearney, Patrick C.,Kim, Byung Gyu,Johnson, Henry W.B.,Aay, Naing,Arcalas, Arlyn,Brown, David S.,Chan, Vicky,Chen, Jeff,Du, Hongwang,Epshteyn, Sergey,Galan, Adam A.,Huynh, Tai P.,Ibrahim, Mohamed A.,Kane, Brian,Koltun, Elena S.,Mann, Grace,Meyr, Lisa E.,Lee, Matthew S.,Lewis, Gary L.,Noguchi, Robin T.,Pack, Michael,Ridgway, Brian H.,Shi, Xian,Takeuchi, Craig S.,Zu, Peiwen,Leahy, James W.,Nuss, John M.,Aoyama, Ron,Engst, Stefan,Gendreau, Steven B.,Kassees, Robert,Li, Jia,Lin, Shwu-Hwa,Martini, Jean-Francois,Stout, Thomas,Tong, Philip,Woolfrey, John,Zhang, Wentao,Yu, Peiwen
, p. 7653 - 7658 (2012)
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl-N-phenylpyrimidin-2-amines
Toviwek, Borvornwat,Suphakun, Praphasri,Choowongkomon, Kiattawee,Hannongbua, Supa,Gleeson, M. Paul
supporting information, p. 4749 - 4754 (2017/09/29)
Reported herein are efforts to profile 4-aryl-N-phenylpyrimidin-2-amines in terms of their anti-cancer activity towards non small-cell lung carcinoma (NSCLC) cells. We have synthesized new 4-aryl-N-phenylpyrimidin-2-amines and assessed them in terms of their cytotoxicity (A549, NCI-H187, MCF7, Vero & KB) and physicochemical properties (logD7.4 and solubility). 13f and 13c demonstrated potent anti-cancer activity in A549 cells (0.2 μM), compared to 0.4 μM for the NSCLC drug Doxorubicin. 13f also displayed low experimental logD7.4 (2.9) and the best solubility (～40 μM). Compounds 13b and 13d showed the best balance of A549 anti-cancer activity and selectivity. 13g showed good activity and selectivity comparable with the anti-cancer drug Doxorubicin.
Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit
Brown, Matthew L.,Aaron, Wade,Austin, Richard J.,Chong, Angela,Huang, Tom,Jiang, Ben,Kaizerman, Jacob A.,Lee, Gary,Lucas, Brian S.,McMinn, Dustin L.,Orf, Jessica,Rong, Minqing,Toteva, Maria M.,Xu, Guifen,Ye, Qiuping,Zhong, Wendy,Degraffenreid, Michael R.,Wickramasinghe, Dineli,Powers, Jay P.,Hungate, Randall,Johnson, Michael G.
scheme or table, p. 5206 - 5209 (2011/10/09)
A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
