Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 6, 2008, Pages 2222-2226

  Chen, Meng Hsin ^a   Fitzgerald, Patricia ^a   Singh, Suresh B ^a   O'Neill, Edward A ^a   Schwartz, Cheryl D ^a   Thompson, Chris M ^a   O'Keefe, Stephen J ^a   Zaller, Dennis M ^a   Doherty, James B ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

MAP Kinase inhibitors; p38

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; AMINO ACID; DIHYDROQUINOLINE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; QUINOLINE DERIVATIVE;

AMINO ACID SUBSTITUTION; ARTICLE; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ASSAY; ENZYME INHIBITION; IN VITRO STUDY; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION;

CRYSTALLOGRAPHY, X-RAY; CYCLIZATION; HUMANS; MOLECULAR STRUCTURE; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN KINASE INHIBITORS; PYRIDAZINES; PYRIMIDINES; QUINOLONES;

EID: 40749129249     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.10.097     Document Type: Article

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18. The calculated log D (pH 7.4) values for compounds 22 and 23 is 2.74; 24 is 4.04; 25 is 3.79; 26 is 3.98; 27 is 4.03; 28 and 29 is 3.78; and 30 is 2.94 according to the ACD program in the ISIS database.
19. The amino group present in compounds 22-30 is protonated at pH 7.4, with the exception of compound 24, according to calculations using the ISIS ACD program. The estimated pKa value for compounds 22 and 23 is 9.43; while the estimated pKa of 24 is 6.71; 25 is 7.72; 26 is 6.71; 27 is 8.30; 28 and 29 is 8.18; and 30 is 8.91.