title: Strategies to mitigate the bioactivation of 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazines: identification of orally bioavailable, efficacious ALK inhibitors.
abstract: Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States. emesaros@cephalon.com
authors.forename: Eugen F
authors.initials: EF
authors.lastname: Mesaros
authors.forename: Tho V
authors.initials: TV
authors.lastname: Thieu
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Wells
authors.forename: Craig A
authors.initials: CA
authors.lastname: Zificsak
authors.forename: Jason C
authors.initials: JC
authors.lastname: Wagner
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Breslin
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Tripathy
authors.forename: James L
authors.initials: JL
authors.lastname: Diebold
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McHugh
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Wohler
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Quail
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.forename: Lihui
authors.initials: L
authors.lastname: Lu
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; 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; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011758:Pyrroles; D014227:Triazines; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases