title: Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase.
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).
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. Electronic address: Eugen.Mesaros@tevapharm.com.
authors: Eugen F
authors: EF
authors: Mesaros
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Thelma S
authors: TS
authors: Angeles
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Mark S
authors: MS
authors: Albom
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Jason C
authors: JC
authors: Wagner
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Lisa D
authors: LD
authors: Aimone
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Weihua
authors: W
authors: Wan
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Lihui
authors: L
authors: Lu
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Zeqi
authors: Z
authors: Huang
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Mark
authors: M
authors: Olsen
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Emily
authors: E
authors: Kordwitz
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: R Curtis
authors: RC
authors: Haltiwanger
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Amy J
authors: AJ
authors: Landis
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Mangeng
authors: M
authors: Cheng
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Bruce A
authors: BA
authors: Ruggeri
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Mark A
authors: MA
authors: Ator
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Bruce D
authors: BD
authors: Dorsey
authors: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors: Gregory R
authors: GR
authors: Ott
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000201:enzymology; D016513:Mice, SCID; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; C543493:pyrrolotriazine-4-one; C032727:piperidine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALCL; ALK; Inhibitors; Kinase; NSCLC; Pyrrolotriazine