title: Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure.
abstract: The design of a novel series of cyclin-dependent kinase (CDK) inhibitors containing a macrocyclic quinoxaline-2-one is reported. Structure-based drug design and optimization from the starting point of diarylurea 2, which we previously reported as a moderate CDK1,2,4,6 inhibitor [J. Biol.Chem.2001, 276, 27548], led to the discovery of potent CDK1,2,4,6 inhibitor that were suitable for iv administration for in vivo study.
authors.affiliation: Department of Medicinal Chemistry, Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. nobuhiko_kawanishi@merck.com
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kawanishi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Shibata
authors.forename: Kaori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kouta
authors.initials: K
authors.lastname: Masutani
authors.forename: Mari
authors.initials: M
authors.lastname: Ikuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirai
mesh_terms: D000818:Animals; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; D011810:Quinoxalines; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6