title: Novel 2,3,4,5-tetrahydro-benzo[d]azepine derivatives of 2,4-diaminopyrimidine, selective and orally bioavailable ALK inhibitors with antitumor efficacy in ALCL mouse models.
abstract: The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA 19380, USA. emesaros@cephalon.com
authors.forename: Eugen F
authors.initials: EF
authors.lastname: Mesaros
authors.forename: Jason P
authors.initials: JP
authors.lastname: Burke
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Parrish
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dugan
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Anzalone
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
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 A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
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; D000818:Animals; D001552:Benzazepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: D001552:Benzazepines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases