Inhibitors of 11βHSD1 have been pursued as  novel therapeutic approach directly targeting the key metabolic risk factors associated with type 2 diabetes, namely glucose dysregulation, insulin resistance, obesity, dyslipidemia and hypertension through lowering of glucocorticoid levels in metabolic target tissues.

The role that glucocorticoids play in negatively regulating the associated metabolic disturbances of diabetes described above is well documented.  The metabolic consequences of elevated systemic glucocorticoids are caused by the actions of glucocorticoids in metabolic target tissues, including most notably liver and (visceral) adipose tissue.

Bioactive glucocorticoids are produced via two distinct systems, by de novo synthesis in the adrenal cortex under control of the hypothalamo-pituitary-adrenal axis, and through local tissue specific intracellular re-activation of inert glucocorticoids by the microsomal enzyme 11βHSD1.

The levels of bioactive glucocorticoids in the liver and (visceral) adipose tissue are chiefly determined by the activity of 11βHSD1. The contribution of 11βHSD1 to overall cortisol generation appears to be of the same magnitude as the cortisol synthesis by the adrenals.

A major difference, however, is that the adrenal cortisol is released into the systemic circulation and distributed throughout the body, whereas the majority of glucocorticoids generated via 11βHSD1are utilized locally in the liver and adipose tissue.

Preliminary clinical studies with inhibitors of 11βHSD1 confirms the beneficial effects of the approach in the treatment of patients with type 2 diabetes with significant reduction in HbA1c, fasting plasma glucose and total cholesterol.

As described above there are remarkable similarities between the pathophysiology of cortisol induced intraocular pressure and that of POAG, and it is only natural to ask if cortisol acts as an important factor in the development of POAG.

There is evidence to support inhibition of 11βHSD1 as a viable therapeutic approach in patients with POAG.  An animal study has demonstrated lowering of IOP after subconjunctival injection of an cortisol antagonist. Furthermore several studies have described the presence of 11βHSD1 in the epithelium of the ciliary body, and studies have demonstrated a 14:1 ratio of cortisol to cortisone in the aqueous humor of the eye, a ratio much higher than seen in plasma, thus supporting an active role of 11βHSD1 in the eye.
 
Exploratory clinical study with carbenoxalone (a model compound inhibiting both 11βHSD1 and 11βHSD2) has demonstrated a decrease in intraocular pressure in healthy people as well as in patients with ocular hypertension.

HPP851 inhibited cortisone from increasing intraocular pressure when compared to the anterior segment that received only cortisone, by 17-20% in cultured human anterior segments.