Jiaqiang Cai

Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity

The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases.

Cathepsin K inhibitors, 2000 – 2004

Cathepsin K is one of eleven cysteine proteases from the papain superfamily known to be expressed in the human genome. Its selective and abundant expression in osteoclasts and critical role in the degradative phase of bone remodelling suggests that selective inhibition of cathepsin K may provide an effective therapy for the treatment of osteoporosis. This hypothesis has generated considerable interest over the past decade in the development of selective cathepsin K inhibitors. Around 190 cathepsin K-related patent applications have been filed since its discovery in rabbit osteoclasts a decade ago; half of which were published in the last two years, indicating the rapidly increasing level of activity in the field. Small-molecule cathepsin K inhibitors have been reported to show efficacy in animal models of osteoporosis. Most recently, the disclosure from Novartis of the successful completion of Phase IIa trials is likely to attract even greater attention to the target. In addition to a role in bone remodelling, evidence supporting the involvement of cathepsin K in spontaneous rupture of atherosclerotic plaque, leading to arterial thrombosis and potentially fatal myocardial infarction, has also been reported recently. This review is focused on recent advances in the development of specific cathepsin K inhibitors, based on the patent literature from January 2000 to June 2004. Given that rapid advances in this period are directly attributable to the availability of crystallographic data, biostructural information related to key enzyme/inhibitor interactions is also briefly summarised.

Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Dioxo-triazines as a novel series of cathepsin K inhibitors.

A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC(50) values of 17nM against catK and >10,000nM in catL, catB and catS assays.