Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase.
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.
Li
Rongshi
R
ChemBridge Research Laboratories and ChemBridge Corporation, 16981 Via Tazon, Suites K and G, San Diego, CA 92127, USA. Rongshi.li@chembridgeresearch.com
Xue
Liquan
L
Zhu
Tong
T
Jiang
Qin
Q
Cui
Xiaoli
X
Yan
Zheng
Z
McGee
Danny
D
Wang
Jian
J
Gantla
Vidyasagar Reddy
VR
Pickens
Jason C
JC
McGrath
Doug
D
Chucholowski
Alexander
A
Morris
Stephan W
SW
Webb
Thomas R
TR
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
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