Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 13, 2004, Pages 3595-3599

  Revesz, Laszlo ^a   Blum, Ernst ^a   Di Padova, Franco E ^a   Buhl, Thomas ^a   Feifel, Roland ^a   Gram, Hermann ^a   Hiestand, Peter ^a   Manning, Ute ^a   Rucklin, Gerard ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTIRHEUMATIC AGENT; COLLAGEN; ENZYME INHIBITOR; IMIDAZO[1,2 B]PYRIDINE DERIVATIVE; IMIDAZOLE DERIVATIVE; LIPOPOLYSACCHARIDE; MITOGEN ACTIVATED PROTEIN KINASE P38; OXAZOLE DERIVATIVE; PYRIDINE DERIVATIVE; THIAZOLE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; CYTOKINE RELEASE; DOSE RESPONSE; DRUG EFFICACY; DRUG SYNTHESIS; MOUSE; NONHUMAN; RAT; RHEUMATOID ARTHRITIS;

ANIMALS; ANTIRHEUMATIC AGENTS; ARTHRITIS, EXPERIMENTAL; COLLAGEN; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; IMIDAZOLES; LIPOPOLYSACCHARIDES; MICE; OXAZOLES; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; TUMOR NECROSIS FACTOR-ALPHA;

EID: 2942560875     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.03.106     Document Type: Article

References (17)

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8. A phosphorylated form of His-p38α MAP kinase (10 ng/well) of murine origin was used and immobilized GST-ATF-2 as substrate in the presence of 120 μM cold ATP
9. Human peripheral blood mononuclear cells from healthy volunteers were incubated with the inhibitor and stimulated with LPS/IFN-γ for 3 h. The supernatants were collected for TNF-α determination by ELISA
10. Eight-week old female OF1 mice were dosed perorally by gavage with solutions of the compounds (10 mg/kg) in DMSO/cornoil. One hour after dosing, LPS (20 mg/kg) was injected iv for stimulation of TNF-α release into plasma. One hour later blood was collected and TNF-α was determined using a mouse specific ELISA
11. AIA: adjuvant induced arthritis. Female Wistar rats were immunized with Mycobacterium tuberculosis at day 0 and dosed with the compounds (2 × 25 mg/kg p.o. per day) from day 14 to 20. Swelling of the joints was measured on day 20
12. CIA: Collagen induced arthritis. Female (WAGxBUF/F1) rats were immunized intradermally with bovine nasal septum type II collagen emulsified in Freund's incomplete adjuvant. Swelling started ∼10 days after immunization. Dosing of compounds started on day 13, when swelling was nearly maximal. Compounds were dosed once (q.d.) daily for 10 days
13. 50 > 2 μM for human P450 isoenzymes CYP1A2, CYP2C9, CYP2D6, CYP3A4
14. 50 > 80 μM for COX-1
15. Profiling continued, if Ames assay and the Comet assay (in vitro with human lymphocytes) were negative
16. 50 (μM) for 32/37/45/59): hJNK1 (0.15/1.9/>10/1.5); hJNK2 (0.03/0.261/4.66/0.047); CDK1 (>10/>10/>10/>10); HER-1 (1.1/0.28/>10/>10); c-Abl (>10/>10/>10/>10); c-Src (>10/8.0/>10/>10); Kdr (1.4/1.7/>10/>10); c-Met (>10/>10/>10/>10); c-Kit (>10/>10/>10/>10); IGF1R (>10/>10/>10/>10); HER-2 (2.0/1.1/>10/>10); c-Raf (8.7/2.1/>10/>10); hEGFR (1.1/0.7/>10/8.7)
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