Pyrroles and other heterocycles as inhibitors of P38 kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 19, 1998, Pages 2689-2694

  De Laszlo, Stephen E ^a   Visco, Denise ^a   Agarwal, Lily ^a   Chang, Linda ^a   Chin, Jayne ^a   Croft, Gist ^a   Forsyth, Amy ^a   Fletcher, Daniel ^a   Frantz, Betsy ^a   Hacker, Candice ^a   Hanlon, William ^a   Harper, Coral ^a   Kostura, Matthew ^a   Li, Bing ^a   Luell, Sylvie ^a   MacCoss, Malcolm ^a   Mantlo, Nathan ^a,c   O'Neill, Edward A ^a   Orevillo, Chad ^a   Pang, Margaret ^a   Parsons, Janey ^a   Rolando, Anna ^a   Sahly, Yousif ^a   Sidler, Kelley ^a   Widmer, W Rick ^b   O'Keefe, Stephen J ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b PURDUE UNIVERSITY   (United States)

^c AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4 FLUOROPHENYL) 5 (4 METHYLSULFINYLPHENYL) 3 (4 PYRIDYL)PYRROLE; 4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 6 (4 FLUOROPHENYL) 2,3 DIHYDRO 5 (4 PYRIDYL)IMIDAZO[2,1 B]THIAZOLE; PYRROLE DERIVATIVE; SKF 86055; UNCLASSIFIED DRUG;

ADJUVANT ARTHRITIS; ANIMAL MODEL; ARTICLE; CROHN DISEASE; DRUG ACTIVITY; DRUG EFFECT; DRUG INDICATION; DRUG SCREENING; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; NONHUMAN; ORAL DRUG ADMINISTRATION; PAW EDEMA; RAT; RHEUMATOID ARTHRITIS;

ANIMALS; ARTHRITIS, EXPERIMENTAL; CA(2+)-CALMODULIN DEPENDENT PROTEIN KINASE; ENZYME INHIBITORS; FURANS; HUMANS; MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PYRAZOLES; PYRROLES; RATS;

ANIMALIA;

EID: 0032491233     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00495-8     Document Type: Article

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25. 19. At each leg three fasted male Sprague-Dawley rats were dosed iv (ethanol/PEG-200 1/9)) or orally (PEG-400/water (7.5/2.5)). Bood samples were withdrawn periodically from a cannula implanted in the right jugular vein. The blood was centrifuged and the plasma treated with acetonitrile, recentrifuged and the supernatant analysed by HPLC. Bioavailability was calculated from the AUC's of the low i.v. and oral doses at 2 and 3mg/kg
26. 20. Adjuvant-induced arthritis (AIA) was induced in 7 week old female Lewis rats (126-169 gm; n = 10) by an intradermal injection of 0.5 mg of M. butyricum in light mineral oil in the left hind foot pad. Body weights, radiographs and foot volumes of both paws were determined on various days (0, 4, 14 and 21). 1 (2, 6, and 20 mg/kg/day p.o. b.i.d.), Indomethacin (1 mg/kg/day p.o. b.i.d.) and vehicle (0.5% methocel) were started on day 0 and continued throughout the experiment. Blood (1 mL) was withdrawn by cardiac puncture under methoxyflurane anesthesia 1 hour or 4 hr after the last dose to determine plasma levels of 1. Rats were euthanized by carbon dioxide inhalation on day 21. The thymus and spleen of all rats were removed and weighed to assess tibio-tarsal joint integrity, radiographic scores were assigned according to an adaptation of a previously described method (Clark R. L.; Cuttino, Jr., J. T.; Anderle, S. K.; Cromatie, W. T.; Schwab, J. H. Arth. Rheum. 1979, 22, 25) by a boarded radiologist who was blinded to treatment. General necropsy noted that abdominal, peritoneal and thoracic cavities were normal. 1 demonstrated efficacy in many of the parameters examined in rat AIA (body weight, paw swelling, and thymus and spleen weights). Indomethacin inhibited the secondary paw swelling by 79% in this experiment.
27. 21. Radiographic scores: 1 20 mg/kg/ b.i.d: 1° paw = 3.6; 2° paw = 1.6. SB 203580 80 mg/kg/day: 1° paw = 6.1 ; 2° paw = 2.6. Indomethacin 1.0 mg/kg/day : 1° paw = 4.9; 2° paw = 2.9.