4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.
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.
Spicer
Julie A
JA
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
Rewcastle
Gordon W
GW
Kaufman
Michael D
MD
Black
Shannon L
SL
Plummer
Mark S
MS
Denny
William A
WA
Quin
John
J
Shahripour
Aurash B
AB
Barrett
Stephen D
SD
Whitehead
Christopher E
CE
Milbank
Jared B J
JB
Ohren
Jeffrey F
JF
Gowan
Richard C
RC
Omer
Charles
C
Camp
Heidi S
HS
Esmaeil
Nadia
N
Moore
Kelley
K
Sebolt-Leopold
Judith S
JS
Pryzbranowski
Sally
S
Merriman
Ronald L
RL
Ortwine
Daniel F
DF
Warmus
Joseph S
JS
Flamme
Cathlin M
CM
Pavlovsky
Alexander G
AG
Tecle
Haile
H
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
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