Therapeutic compounds for Cushing’s syndrome: a patent review (2012-2016)

ABSTRACT

Introduction: Endogenous Cushing’s syndrome (CS) is a set of disorders caused by chronic exposure to excess glucocorticoids induced by neuroendocrine tumors in pituitary, adrenals, and infrequently other sites (ectopic ACTH syndrome). Due to various comorbidities, CS patients exhibit higher risks of cardiovascular diseases and thus increased mortality. Pharmaceutical therapy is an important constituent of treatment regimen.

Areas covered: Patents published since 2012 are reviewed, which claim therapeutic compounds interfering with ACTH secretion and down-stream signal transduction, inhibiting cortisol biosynthesis and antagonizing glucocorticoid receptors. Advances focus on a) new analogues with improved efficacy and PK properties or less off-target toxicity; b) existing drugs (candidates) being repurposed to treat CS; and c) novel strategies such as selective inhibition of CYP11B1.

Expert opinion: New compounds against established targets need to be developed because current drugs lack selectivity leading to off-target toxicity. Selective inhibition of CYP11B1 is a novel alternative strategy and is potentially versatile in controlling all types of hypercortisolism. Selective multi-targeting enzymes in steroidogenesis network is promising due to potential synergistic effects. However, doses toward each targets are not feasible to adjust because the corresponding intrinsic potencies are rigid. Targeting PRKACA mutations is promising in treating CS caused by adrenal adenomas.

KEYWORDS:

• Cortisol
• Cushing’s syndrome
• CYP11B1 inhibitors
• hypercortisolism
• multi-targeting
• patents
• pharmaceutical therapies
• selectivity

Article highlights

• Nearly all nodes in the life cascade of cortisol have been systemically targeted: regulation of secretion, biosynthesis and biological effects implementation.

• Currently used drugs in treating Cushing’s syndrome are commonly deficient of selectivity and need to be improved accordingly.

• Selective inhibitors of CYP11B1 are novel alternatives and could be employed versatilely in controlling hypercortisolism.

• Multi-targeting compounds could render potential synergistic effects and improve the compliance of patients, however, their factual doses toward different targets cannot be flexibly adjusted because the corresponding potencies are intrinsically rigid.

• Mutations in the catalytic subunit α of PKA is a promising target in treating Cushing’s syndrome caused by adrenal adenomas. This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.