Rheumatoid Arthritis: Xu W

Tu G, Xu W, Huang H, Li S. · Department of Medicinal Chemistry, School of Pharmaceutical Sciences, ShanDong University, 44, West Culture Road, Ji'nan, 250012, P.R. China. · Curr Med Chem. · Pubmed #18537616 No free full text.

Abstract: Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years.With the failure of these inhibitors in clinical trials,more efforts have been directed to the design of specific inhibitors with different Zn-binding groups. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.

Culverhouse RC, Suarez BK, Beckmann L, Chen P, Chen YS, Chiu YF, Chang-Claude J, Dempfle A, Hein R, Kazma R, Lebrec JJ, Lee S, Lim S, Maher BS, Park T, Perdry H, Wang KS, Wolkow PP, Xu W. · Department of Medicine, Washington University School of Medicine, 600 South Euclid, St. Louis, MO 63110, USA. · Genet Epidemiol. · Pubmed #18046766 No free full text.

Abstract: This paper summarizes the contributions of group 8 to the Genetic Analysis Workshop 15. Group 8 focused on ways to address the possibility that genetic and environmental effects on phenotype may not be independent, but instead may interact in ways that could play important roles in determining phenotype. Among the eight contributors to this group, all three data sets (expression data, rheumatoid arthritis data, and simulated data) were analyzed. Contributions to this section fell into the two broad categories of refining the data (e.g. stratifying or weighting based on a covariate value) and explicitly modeling the interactions. The contributions also illustrate that there are at least two possible goals for such studies. One goal is simply to identify factors contributing to phenotype in the presence of interactions that might mask the signal to univariate methods. A related but distinct goal is to characterize an interaction (e.g. to determine if the interaction is significant).

Xu W, Li Q. · Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shan Dong University, 44 West Culture Road, Ji'nan 250012, P.R.China. · Curr Med Chem Anticancer Agents. · Pubmed #15992355 No free full text.

Abstract: Aminopeptidase N (APN; CD13) is a member of zinc-containing ectoenzymes family involved in the degradation of neutral or basic amino acids (Ala>Phe>Leu>Gly) from N-terminal of bioactive peptides and amide or arylamide derivatives of amino acids. The expression of APN being up regulated has been implicated in the pathogenesis of a variety of diseases such as cancer, leukemia, diabetic nephropathy, and rheumatoid arthritis. Thus, APN inhibitors (APNIs) are expected to be useful for the treatment of these disorders. This article reviews briefly the structure characteristic and possible function of APN. The proposed biomolecular structures and mechanism of action used in the design of APNIs are thoroughly covered. Major emphasis is on recently published potent, small molecular weight APNIs and their essential structure activity relationship (SAR). Finally, available clinical results of compounds in development are summarized in this review.

Xu W, Lan H, Hu P, Bull SB, Greenwood CM. · Department of Biostatistics, Princess Margaret Hospital, Toronto, Ontario, 610 University Avenue, Room 15-507, Toronto, Ontario, Canada M5G 2M9. · BMC Proc. · Pubmed #18466580 links to  free full text

Abstract: ABSTRACT : Focusing on chromosome 1, a recursive partitioning linkage algorithm (RP) was applied to perform linkage analysis on the rheumatoid arthritis NARAC data, incorporating covariates such as HLA-DRB1 genotype, age at onset, severity, anti-cyclic citrullinated peptide (anti-CCP), and life time smoking. All 617 affected sib pairs from the ascertained families were used, and an RP linkage model was used to identify linkage possibly influenced by covariates. This algorithm includes a likelihood ratio (LR)-based splitting rule, a pruning algorithm to identify optimal tree size, and a bootstrap method for final tree selection.The strength of the linkage signals was evaluated by empirical p-values, obtained by simulating marker data under null hypothesis of no linkage. Two suggestive linkage regions on chromosome 1 were detected by the RP linkage model, with identified associated covariates HLA-DRB1 genotype and age at onset. These results suggest possible gene x gene and gene x environment interactions at chromosome 1 loci and provide directions for further gene mapping.

Zhang Y, Hegen M, Xu J, Keith JC, Jin G, Du X, Cummons T, Sheppard BJ, Sun L, Zhu Y, Rao VR, Wang Q, Xu W, Cowling R, Nickerson-Nutter CL, Gibbons J, Skotnicki J, Lin LL, Levin J. · Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. · Int Immunopharmacol. · Pubmed #15531300 No free full text.

Abstract: TNF-alpha converting enzyme (TACE) is a validated therapeutic target for the development of oral tumor necrosis factor-alpha (TNF-alpha) inhibitors. Here we report the pre-clinical results and characterization of a selective and potent TACE inhibitor, (2R, 3S)-2-([[4-(2-butynyloxy)phenyl]sulfonyl]amino)-N,3-dihydroxybutanamide (TMI-2), in various in vitro and in vivo assays. TMI-2 is a potent TACE inhibitor in an enzymatic FRET assay (IC50=2 nM). It is more than 250-fold selective over MMP-1, -7, -9, -14, and ADAM-10 in vitro. In cell-based assays and human whole blood, TMI-2 inhibits lipopolysaccharide (LPS)-induced TNF secretion with IC50s<1 uM. Importantly, TMI-2 inhibits the spontaneous release of TNF-alpha in human synovium tissue explants of rheumatoid arthritis patients with an IC50 of 0.8 microM. In vivo, TMI-2 potently inhibits LPS-induced TNF-alpha production in mice (ED50=3 mg/kg). In the adjuvant-induced arthritis (AIA) model in rats, treatment with TMI-2 at 30 mg/kg and 100 mg/kg p.o. b.i.d. was highly effective in reducing joint arthritis scores. In a semi-therapeutic collagen-induced arthritis (CIA) model in mice, TMI-2 is highly effective in reducing disease severity scores after oral treatment at 100 mg/kg twice per day. In summary, TMI-2 is a potent and selective TACE inhibitor that inhibits TNF-alpha production and reduces the arthritis scores in pre-clinical models. TMI-2 represents a novel class of TACE inhibitors that may be effective and beneficial in the treatment of rheumatoid arthritis as well as other TNF-mediated inflammatory autoimmune diseases.