623155-19-1Relevant articles and documents
Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine
Walter, Niklas M.,Wentsch, Heike K.,Bührmann, Mike,Bauer, Silke M.,D?ring, Eva,Mayer-Wrangowski, Svenja,Sievers-Engler, Adrian,Willemsen-Seegers, Nicole,Zaman, Guido,Buijsman, Rogier,L?mmerhofer, Michael,Rauh, Daniel,Laufer, Stefan A.
, p. 8027 - 8054 (2017/10/18)
We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.
Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases
Liu, Chunjian,Lin, James,Wrobleski, Stephen T.,Lin, Shuqun,Hynes, John,Wu, Hong,Dyckman, Alaric J.,Li, Tianle,Wityak, John,Gillooly, Kathleen M.,Pitt, Sidney,Shen, Ding Ren,Zhang, Rosemary F.,McIntyre, Kim W.,Salter-Cid, Luisa,Shuster, David J.,Zhang, Hongjian,Marathe, Punit H.,Doweyko, Arthur M.,Sack, John S.,Kiefer, Susan E.,Kish, Kevin F.,Newitt, John A.,McKinnon, Murray,Dodd, John H.,Barrish, Joel C.,Schieven, Gary L.,Leftheris, Katerina
experimental part, p. 6629 - 6639 (2010/12/18)
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
CYCLOPROPYL BENZAMIDE DERIVATIVES AS INTERMEDIATES FOR CYTOKINE INHIBITORS
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Page/Page column 16, (2009/12/23)
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein Qa is as defined in the specification, the compounds being useful in the preparation of therapeutic agents, in particular cytokine inhibitors. Novel compounds of formula (I) are also provided.
