Piperidine-3, 4-diol and piperidine-3-ol derivatives of pyrrolo[2, 1-f][1, 2, 4]triazine as inhibitors of anaplastic lymphoma kinase. Issue 5 (1st March 2015)

• Record Type: Journal Article
• Authors: Mesaros, Eugen F.; Angeles, Thelma S.; Albom, Mark S.; Wagner, Jason C.; Aimone, Lisa D.; Wan, Weihua; Lu, Lihui; Huang, Zeqi; Olsen, Mark; Kordwitz, Emily; Haltiwanger, R. Curtis; Landis, Amy J.; Cheng, Mangeng; Ruggeri, Bruce A.; Ator, Mark A.; Dorsey, Bruce D.; Ott, Gregory R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 5(2015)
• Page Start: 1047
• Page End: 1052
• Publication Date: 2015-03-01
• Subjects: Kinase -- ALK -- ALCL -- NSCLC -- Inhibitors -- Pyrrolotriazine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.019
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The diastereoselective synthesis and biological activity of piperidine-3, 4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3, 4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans -4-aryl-piperidine-3-ols (22 ) were more potent than the cis diastereomers (20 ).