Diabetes R & D Pipeline: 11beta-hsd1 Inhibitors

Summary

Summary

11beta-HSD1 (11beta-hydroxysteroid dehydrogenase type 1) antagonists are insulin sensitizers. 11beta-HSD1 is an enzyme that converts inactive cortisone into potent, biologically active hormone, cortisol. This conversion occurs within cells of key metabolic tissues including liver, adipose tissue, muscle tissue, and pancreas. Cortisol elevates blood glucose levels by increasing glucose production in liver, and by inhibiting uptake and disposal of glucose in muscle and adipose tissues. Consequently, 11beta-HSD1 mediated production of cortisol contributes to insulin resistance, development of type 2 diabetes, and associated cardiovascular diseases

Preclinical studies have demonstrated that transgenic mice overexpressing 11beta-HSD1-selectively in adipose tissue develop type 2 diabetes and visceral obesity, in comparison to 11beta-HSD1 knockout mouse, which displays normoglycemia and normal weight.

11beta-HSD1 inhibitors were found to increase insulin sensitivity and glucose tolerance and to have anti-obesity effects. In addition, atherosclerotic plaques in apoE knockout mice were improved after treatment with 11beta- HSD1 inhibitors.

11beta-HSD1 inhibitors appear to be attractive research and development products for the treatment of type 2 diabetes because a large number of major biotechnology and pharmaceutical companies are involved in their development, and this pipeline, although very young, already has 70% of products in clinical stage of development.

Analysis reveals that total of 10 products based on 11beta-HSD1 inhibitors are undergoing development for the treatment of diabetes by 10 companies. Seven out of 11 companies are major biotechnology and pharmaceutical companies. In addition, at least eight more companies are involved in development of 11beta-HSD1 inhibitors. Majority (70%) of 11beta-HSD1 inhibitors are in Phase I clinical trials. Roche Holding, Ltd. (Switzerland) domineers in this field. All 6 US patents covering 11beta-HSD1 inhibitors, issued so far, holds Hoffman-La Roche, Inc. (USA), a business unit of Roche Holding, Ltd.

(Switzerland). Out of 15 applications for 11beta-HSD1 inhibitors, registered by the US Patent Office, 11 belong to Hoffman-La Roche, Inc. (USA). So far, development of three 11 beta-HSD1 inhibitors was terminated, including DIO-902 in April 2009, due to the termination of DiObex, Inc. (USA) business activities, INCB 20817 in 2008 (replaced with and INCB13739) and PF-915275 (N-(Pyridin-2-yl) arylsulfonamide inhibitor of i11beta-HSD1) in 2007 (without explanation). In addition, the USA Phase II clinical trial with JTT-654 was terminated three months after its start.

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