title: 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity.
abstract: A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., West Chester, Pennsylvania 19380, USA. gott@cephalon.com
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Wells
authors.forename: Tho V
authors.initials: TV
authors.lastname: Thieu
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Quail
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Lisko
authors.forename: Eugen F
authors.initials: EF
authors.lastname: Mesaros
authors.forename: Diane E
authors.initials: DE
authors.lastname: Gingrich
authors.forename: Arup K
authors.initials: AK
authors.lastname: Ghose
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.forename: Lihui
authors.initials: L
authors.lastname: Lu
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C562237:N-(2-(2-(4-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methoxyphenylamino)pyrrolo(2,1-f)(1,2,4)triazin-7-yl)phenyl)-N-methylmethanesulfonamide; D011758:Pyrroles; D013449:Sulfonamides; D014227:Triazines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases