Hybrid-designed inhibitors of p38 MAP kinase utilizing N-arylpyridazinones

Journal of Medicinal Chemistry

Volumn 46, Issue 3, 2003, Pages 349-352

  Colletti, Steven L ^a   Frie, Jessica L ^a   Dixon, Elizabeth C ^a   Singh, Suresh B ^a   Choi, Bernard K ^a   Scapin, Giovanna ^a   Fitzgerald, Catherine E ^a   Kumar, Sanjeev ^a   Nichols, Elizabeth A ^a   O'Keefe, Stephen J ^a   O'Neill, Edward A ^a   Porter, Gene ^a   Samuel, Koppara ^a   Schmatz, Dennis M ^a   Schwartz, Cheryl D ^a   Shoop, Wesley L ^a   Thompson, Chris M ^a   Thompson, James E ^a   Wang, Ruixiu ^a   Woods, Andrea ^a   Zaller, Dennis M ^a   Doherty, James B ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 5 (2,6 DICHLOROPHENYL) 2 (2,4 DIFLUOROPHENYLTHIO)PYRIMIDO[1,6 B]PYRIDAZIN 6 ONE; ETANERCEPT; IMIDAZOPYRIDYL N PYRIDAZINONE DERIVATIVE; INFLIXIMAB; INTERLEUKIN 1BETA; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; N (2 CHLOROPHENYL)PYRIDAZINONE DERIVATIVE; N (2 TOLYL)PYRIDAZINONE DERIVATIVE; N (2,6 DICHLOROPHENYL)PYRIDAZINONE DERIVATIVE; PYRIDAZINONE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BROMINATION; DRUG DESIGN; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HYBRIDIZATION; HYDROGEN BOND; IC 50; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; ENZYME INHIBITORS; MICE; MITOGEN-ACTIVATED PROTEIN KINASES; MODELS, MOLECULAR; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PYRIDAZINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0037472796     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm025585h     Document Type: Article

References (31)

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30. It is speculated that the smaller o-fluorine atom of 19 and 28 allows the rotation of the aryl ring into the plane of the imidazopyridine, both moieties of which may delocalize π-electron density more easily into the oxidized pyridazinone ring and N-aryl moiety. This increased planarity, based on a lowered ground-state energy of the molecule, could result in a higher energy barrier toward enzyme binding conformation that requires orthogonal aryl rings (Figure 2).
31. 50). This method does not address active metabolites.