4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Research Abstract Details 

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4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Abstract Text:

Julie A Spicer,Gordon W Rewcastle,Michael D Kaufman,Shannon L Black,Mark S Plummer,William A Denny,John Quin,Aurash B Shahripour,Stephen D Barrett,Christopher E Whitehead,Jared B J Milbank,Jeffrey F Ohren,Richard C Gowan,Charles Omer,Heidi S Camp,Nadia Esmaeil,Kelley Moore,Judith S Sebolt-Leopold,Sally Pryzbranowski,Ronald L Merriman,Daniel F Ortwine,Joseph S Warmus,Cathlin M Flamme,Alexander G Pavlovsky,Haile Tecle,Julie A Spicer,Gordon W Rewcastle,Michael D Kaufman,Shannon L Black,Mark S Plummer,William A Denny,John Quin,Aurash B Shahripour,Stephen D Barrett,Christopher E Whitehead,Jared B J Milbank,Jeffrey F Ohren,Richard C Gowan,Charles Omer,Heidi S Camp,Nadia Esmaeil,Kelley Moore,Judith S Sebolt-Leopold,Sally Pryzbranowski,Ronald L Merriman,Daniel F Ortwine,Joseph S Warmus,Cathlin M Flamme,Alexander G Pavlovsky,Haile Tecle,

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.

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Publishing Authors By Initials

JA Spicer,GW Rewcastle,MD Kaufman,SL Black,MS Plummer,WA Denny,J Quin,AB Shahripour,SD Barrett,CE Whitehead,JB Milbank,JF Ohren,RC Gowan,C Omer,HS Camp,N Esmaeil,K Moore,JS Sebolt-Leopold,S Pryzbranowski,RL Merriman,DF Ortwine,JS Warmus,CM Flamme,AG Pavlovsky,H Tecle,JA Spicer,GW Rewcastle,MD Kaufman,SL Black,MS Plummer,WA Denny,J Quin,AB Shahripour,SD Barrett,CE Whitehead,JB Milbank,JF Ohren,RC Gowan,C Omer,HS Camp,N Esmaeil,K Moore,JS Sebolt-Leopold,S Pryzbranowski,RL Merriman,DF Ortwine,JS Warmus,CM Flamme,AG Pavlovsky,H Tecle,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of medicinal chemistry

VOLUME: 50

Page Numbers: 5090-102

Journal Abbreviation: J. Med. Chem.

ISSN: 0022-2623

DAY: 19

MONTH: 09

YEAR: 2007

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Information

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LANGUAGE: eng

NlmUniqueID: 9716531

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: pharmacology

Chemical & Substance for Abstract: 4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase. Information

Substance Name: Extracellular Signal-Regulated MAP Kinas

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for 4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.

AFFILIATION: 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

Country: United States

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MEDLINETA: J Med Chem

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