Rheumatoid Arthritis: Feifel R

Schlapbach A, Feifel R, Hawtin S, Heng R, Koch G, Moebitz H, Revesz L, Scheufler C, Velcicky J, Waelchli R, Huppertz C. · Novartis Institutes for BioMedical Research, global Discovery Chemistry, WSJ-88.508, CH-4002 Basel, Switzerland. · Bioorg Med Chem Lett. · Pubmed #18945615 No free full text.

Abstract: Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.

Busso N, Frasnelli M, Feifel R, Cenni B, Steinhoff M, Hamilton J, So A. · Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Arthritis Rheum. · Pubmed #17195212 links to  free full text

Abstract: OBJECTIVE: Protease-activated receptor 2 (PAR-2) activation has been linked to pro- and antiinflammatory cellular responses. We undertook this study to explore the importance of PAR-2 activation in 4 murine models of arthritis and to analyze the expression of PAR-2 in human arthritic synovium. METHODS: Zymosan-induced arthritis (ZIA), K/BxN serum-induced arthritis, and Freund's complete adjuvant (CFA)-induced arthritis were generated in naive PAR-2(-/-) mice and PAR-2(+/+) littermates. Antigen-induced arthritis (AIA) was generated in immunized mice using methylated bovine serum albumin (mBSA). The severity of arthritis was assessed by clinical scoring, technetium uptake measurement, and histologic analysis. Immune responses to mBSA were also evaluated from AIA. The expression of PAR-2 in synovial tissues from rheumatoid arthritis (RA) and osteoarthritis (OA) patients was compared. RESULTS: In AIA, arthritis was significantly decreased in PAR-2-deficient mice and was associated with decreased levels of anti-mBSA IgG antibodies and lymph node cell proliferation. No difference in arthritis severity was seen in mice with ZIA, K/BxN serum-induced arthritis, and CFA-induced arthritis. Synovial biopsy specimens from RA patients demonstrated significantly increased expression of PAR-2 compared with those from OA patients. CONCLUSION: PAR-2 deficiency was found to modulate articular inflammation in murine models of arthritis that require prior immunization and was associated with reduced levels of anti-mBSA IgG and lymph node cell proliferation in AIA. Expression of PAR-2 in RA synovium was significantly higher than that in OA synovium, and this suggests that PAR-2 is implicated in the pathogenesis of immune-mediated forms of arthritis.

Revesz L, Blum E, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Neumann U, Rucklin G. · Novartis Institutes for BioMedical Research, Global Discovery Chemistry, CH-4002 Basel, Switzerland. · Bioorg Med Chem Lett. · Pubmed #16249085 No free full text.

Abstract: A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.

Revesz L, Blum E, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Rucklin G. · Novartis Institutes for BioMedical Research, Arthritis and Bone Metabolism, CH-4002 Basel, Switzerland. · Bioorg Med Chem Lett. · Pubmed #15177483 No free full text.

Abstract: Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.

Revesz L, Blum E, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Rucklin G. · Novartis Institutes for BioMedical Research, Arthritis & Bone Metabolism, CH-4002 Basel, Switzerland. · Bioorg Med Chem Lett. · Pubmed #15177482 No free full text.

Abstract: A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.