No abstract

Objective. The transcription of several cytokines, cell adhesion molecules, and enzymes involved in the inflammatory and destructive mechanisms of rheumatoid arthritis is dependent on nuclear factor B (NF-B). Because IB kinase (IKK) is critical in transducing the signal-inducible activation of NF-B, we examined whether the highly selective and orally bioavailable IKK inhibitor BMS-345541 is efficacious against collagen-induced arthritis (CIA) in mice.Methods. Arthritis in DBA/1LacJ male mice was induced by subcutaneous immunization with bovine type II collagen on day 0 and day 21. BMS-345541 was administered perorally daily, either prophylactically (before disease onset) or therapeutically (after disease onset). Clinical assessment of the incidence and severity of disease was conducted throughout the study, and histologic evaluation was performed at the time of study termination (day 42).Results. When administered prophylactically, BMS-345541 (in a dose range of 10-100 mg/kg) was effective, in a dose-dependent manner, in reducing the incidence of disease and inhibiting clinical signs of disease. Histologic evaluation of the joints showed that both inflammation and joint destruction were blocked by the IKK inhibitor. Message levels of interleukin-1␤ in the joints were also dose-dependently inhibited in the mice that received BMS-345541. Dose-dependent efficacy in terms of both disease severity and histologic end points was observed with the therapeutic dosing regimen of BMS-345541, with use of the 100-mg/kg dose resulting in resolution of disease.Conclusion. IKK plays a key role in CIA in mice, and inhibitors of this enzyme represent a promising target for the development of novel agents to treat rheumatoid arthritis and other inflammatory diseases. BMS-345541 represents the first example of an inhibitor of IKK that has antiinflammatory activity in vivo.

The crystal structure of the ligand-binding domain of RARb, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARb to bind more bulky agonists. Accordingly, we identified a ligand that shows RARb selectivity with a 100-fold higher affinity to RARb than to a or c isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARa, c antagonist and an RARb agonist. In addition, we demonstrate how to generate an RARb antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARb-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARb in vitro and in animal models.

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Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of beta-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.