title: 4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.
abstract: A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
authors: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. j.spicer@auckland.ac.nz
authors: Julie A
authors: JA
authors: Spicer
authors: Gordon W
authors: GW
authors: Rewcastle
authors: Michael D
authors: MD
authors: Kaufman
authors: Shannon L
authors: SL
authors: Black
authors: Mark S
authors: MS
authors: Plummer
authors: William A
authors: WA
authors: Denny
authors: John
authors: J
authors: Quin
authors: Aurash B
authors: AB
authors: Shahripour
authors: Stephen D
authors: SD
authors: Barrett
authors: Christopher E
authors: CE
authors: Whitehead
authors: Jared B J
authors: JB
authors: Milbank
authors: Jeffrey F
authors: JF
authors: Ohren
authors: Richard C
authors: RC
authors: Gowan
authors: Charles
authors: C
authors: Omer
authors: Heidi S
authors: HS
authors: Camp
authors: Nadia
authors: N
authors: Esmaeil
authors: Kelley
authors: K
authors: Moore
authors: Judith S
authors: JS
authors: Sebolt-Leopold
authors: Sally
authors: S
authors: Pryzbranowski
authors: Ronald L
authors: RL
authors: Merriman
authors: Daniel F
authors: DF
authors: Ortwine
authors: Joseph S
authors: JS
authors: Warmus
authors: Cathlin M
authors: CM
authors: Flamme
authors: Alexander G
authors: AG
authors: Pavlovsky
authors: Haile
authors: H
authors: Tecle
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; C524270:4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide; D000577:Amides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D011728:Pyridones; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2