Indole-based heterocyclic inhibitors of p38α MAP kinase: Designing a conformationally restricted analogue

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 18, 2003, Pages 3087-3090

  Mavunkel, Babu J ^a   Chakravarty, Sarvajit ^a   Perumattam, John J ^a   Luedtke, Gregory R ^a   Liang, Xi ^a   Lim, Don ^a   Xu, Yong Jin ^a   Laney, Maureen ^a   Liu, David Y ^b   Schreiner, George F ^a   Lewicki, John A ^c   Dugar, Sundeep ^a  

^a SCIOS INC   (United States)

^b FIBROGEN INC   (United States)

^c Osel Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; ENZYME; HETEROCYCLIC COMPOUND; INDOLE; INTERLEUKIN 1; P38 ALPHA MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CHRONIC INFLAMMATION; CONFORMATIONAL TRANSITION; INFLAMMATION; RHEUMATOID ARTHRITIS; STRUCTURE ACTIVITY RELATION;

EID: 12444323524     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00653-X     Document Type: Article

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19. +: 320.
20. 50 is the concentration of compound which reduced the incorporation of ATP into the substrate by 50%, when compared with the no-inhibitor control reactions.
21. +: 378] were synthesized using appropriate modifications of the procedure described for the synthesis of 1.
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25. D=+47°, (c 1.00, methanol). The enantiomerically pure salt was neutralized by dissolution in 350 mL, methylene chloride and treatment with 1 N NaOH, (3×100 mL) drying of the organic layer over anhydrous magnesium sulfate and filtration was followed by concentration on a rotary evaporator to give 18.6 g of the free base of trans-2S,5R-dimethyl-4-benzylpiperazine.
26. D=-48.1° (c 1.00, methanol). The enantiomerically pure salt was neutralized by dissolution in 450 mL, methylene chloride and treatment with 1 N NaOH, (3×100 mL) drying of the organic layer over anhydrous magnesium sulfate and filtration was followed by concentration on a rotary evaporator to give 15.4 g of the free base of trans-2R,5S-dimethyl-4-benzylpiperazine.
27. Computational methods: The docking, conformation searching and energy calculation were done using the MOE software package. Systematic conformation searches were carried out in lower 7 kcal/mol energy windows and potential energies of resulting conformations were calculated using the MMFF94s force field. After removing the original ligand and water molecules, the ATP pocket of published crystal structure 1BL6 was used in the docking studies reported in this publication.