title: Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase.
abstract: Dysregulation of the anaplastic lymphoma kinase (ALK) is implicated in a variety of cancers. A series of tetrahydropyrido[2,3-b]pyrazines was constructed as ring-constrained analogs of a known aminopyridine kinase scaffold. Chemistry was developed to rapidly elaborate the SAR, structural elements impacting ALK inhibitory activity were exploited, and kinase selective analogs were identified that inhibit ALK with IC(50) values approximately 10 nM (enzyme) and approximately 150 nM (cell).
authors.affiliation: Cephalon, Inc. West Chester, PA 19380-4245, USA. kmilkiew@cephalon.com
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
authors.forename: Linda R
authors.initials: LR
authors.lastname: Weinberg
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.forename: Arup K
authors.initials: AK
authors.lastname: Ghose
authors.forename: Renee C
authors.initials: RC
authors.lastname: Roemmele
authors.forename: Jay P
authors.initials: JP
authors.lastname: Theroff
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.forename: Craig A
authors.initials: CA
authors.lastname: Zificsak
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases