5-Amino-pyrazoles as potent and selective p38α inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 23, 2010, Pages 6886-6889

  Das, Jagabandhu ^a   Moquin, Robert V ^a   Dyckman, Alaric J ^a   Li, Tianle ^a   Pitt, Sidney ^a   Zhang, Rosemary ^a   Shen, Ding Ren ^a   McIntyre, Kim W ^a   Gillooly, Kathleen ^a   Doweyko, Arthur M ^a   Newitt, John A ^a   Sack, John S ^a   Zhang, Hongjian ^a   Kiefer, Susan E ^a   Kish, Kevin ^a   McKinnon, Murray ^a   Barrish, Joel C ^a   Dodd, John H ^a   Schieven, Gary L ^a   Leftheris, Katerina ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Amino pyrazoles; P38 Inhibitors

Indexed keywords

5 AMINOPYRAZOLE; LIPOPOLYSACCHARIDE; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PYRAZOLE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; MOLECULAR DOCKING; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; MICE; MITOGEN-ACTIVATED PROTEIN KINASE 14; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

MURINAE;

EID: 78149284336     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.10.034     Document Type: Article

References (15)

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11. For a description of the biological assays, and X-ray crystal structure determination protocol, see: J. Hynes Jr., A.J. Dyckman, S. Lin, S.T. Wrobleski, H. Wu, K.M. Gillooly, H. Lonial, D. Loo, K.W. McIntyre, S. Pitt, D.R. Shen, D.J. Shuster, X. Zhang, K. Behnia, P.H. Marathe, A. Doweyko, J. Barrish, J. Dodd, G. Schieven, and K. Leftheris J. Med. Chem. 51 2008 4
12. For additional 5-substitution SAR in this series, see: Dyckman, A. J.; Li, T.; Das, J.; Moquin, R. V. M.; Pitt, S.; Zhang, R.; Shen, D. R.; McKinnon, M.; McIntyre, K. W.; Gillooly, K.; Shuster, D.; Taylor, T.; Doweyko, A. M.; Sack, J. S.; Zhang, H.; Marathe, P.; Barrish, J. C.; Dodd, J. H.; Leftheris, K., manuscript in preparation.
13. Rat, Mouse and Human Liver Microsome Stability Assays: Rat and mouse Microsomes were purchased from XenoTech (Kansas City, KS). The human microsomes were purchased from In Vitro Technology (Baltimore, MD) and were pooled from 10 individual donors. The rates of oxidative metabolism were measured in triplicate under the following conditions: compound 2j, 3 μM final concentration; final microsomal protein concentration approximately 1 mg/mL; NADPH 1 mM; pH 7.4 potassium phosphate buffer, 56 mM. Incubations were performed at 37 °C and were initiated by the addition of the substrate. Aliquot (100 μL) of the incubation were quenched at 0, and 10 min by the addition of 1 volume of acetonitrile. Results from 10-min incubations were used for the rate calculations. Sample were analyzed by the LC/MS/MS assay for the amount of the drug remaining at any time point. The percent metabolized was calculated based on the disappearance of the parent compound.
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15. The X-ray coordinates have been deposited with the RCSB Protein Data Bank (RCSB ID Code: rcsb060940 and PDB ID Code: 30CG).