title: Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase.
abstract: Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.
authors.affiliation: ChemBridge Research Laboratories and ChemBridge Corporation, 16981 Via Tazon, Suites K and G, San Diego, CA 92127, USA. Rongshi.li@chembridgeresearch.com
authors.forename: Rongshi
authors.initials: R
authors.lastname: Li
authors.forename: Liquan
authors.initials: L
authors.lastname: Xue
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cui
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yan
authors.forename: Danny
authors.initials: D
authors.lastname: McGee
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Vidyasagar Reddy
authors.initials: VR
authors.lastname: Gantla
authors.forename: Jason C
authors.initials: JC
authors.lastname: Pickens
authors.forename: Doug
authors.initials: D
authors.lastname: McGrath
authors.forename: Alexander
authors.initials: A
authors.lastname: Chucholowski
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D011728:Pyridones; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases