Synthesis and SAR of p38α MAP kinase inhibitors based on heterobicyclic scaffolds

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 18, 2007, Pages 5019-5024

  Murali Dhar, T G ^a   Wrobleski, Stephen T ^a   Lin, Shuqun ^a   Furch, Joseph A ^a   Nirschl, David S ^a   Fan, Yi ^a   Todderud, Gordon ^a   Pitt, Sidney ^a   Doweyko, Arthur M ^a   Sack, John S ^a   Mathur, Arvind ^a   McKinnon, Murray ^a   Barrish, Joel C ^a   Dodd, John H ^a   Schieven, Gary L ^a   Leftheris, Katerina ^a  

^a BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

Author keywords

MAP kinase inhibitors; p38 ; TNF ; X ray co crystallography

Indexed keywords

IMIDAZO[1,5 A]PYRAZINE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE 14; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38ALPHA INHIBITOR; PYRAZINE DERIVATIVE; PYRAZOLO[4,3 C]PYRIDINE DERIVATIVE; PYRIDINE DERIVATIVE; PYRIDO[3,4 D]PYRIMIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; BICYCLO COMPOUND; HETEROCYCLIC COMPOUND; MITOGEN ACTIVATED PROTEIN KINASE P38; PROTEIN KINASE INHIBITOR;

ARTICLE; BINDING AFFINITY; CYTOKINE PRODUCTION; DRUG BINDING; DRUG POTENCY; DRUG RESEARCH; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROGEN BOND; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; SYNTHESIS;

BICYCLO COMPOUNDS; CRYSTALLOGRAPHY, X-RAY; HETEROCYCLIC COMPOUNDS; MODELS, MOLECULAR; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN KINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34547921999     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.07.029     Document Type: Article

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21. 2, 0.015% Brij35, and 4 mM DTT). The reaction was initiated by the combination of bacterially expressed, activated p38 with substrates and test compounds. The reaction mixture was incubated at room temperature for 60 min and terminated by adding 30 μl of 35 mM EDTA to each sample. The reaction mixture was analyzed on the Caliper LabChip 3000 by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data were calculated by comparison to no enzyme control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. The final concentrations of reagents in the assays are ATP, 20 μM; FL-IPTSPITTTYFFFKKK-OH, 1.5 μM; p38, 6 nM; and DMSO, 0.6%.
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