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Drug design strategies for Cushing’s syndrome

ABSTRACT Introduction: Cushing’s syndrome (CS) is a metabolic disorder caused by chronic hypercortisolism. CS is associated with cardiovascular, metabolic, skeletal and psychological dysfunctions and can be fatal if left untreated. The first-line treatment for all forms of CS is a surgery. However, medical therapy has to be chosen if surgical resection is not an option or is deemed ineffective. Currently available therapeutics are either not selective and have side effects or are only available as an injection (pasireotide). Areas covered: The authors discuss the recent drug developments for the medical treatment of CS through two validated molecular targets. Specifically, the authors look at selective inhibitors of CYP11B1 that reduce cortisol production by inhibiting steroid 11beta-hydroxylase and glucocorticoid receptor (GR) antagonists that interrupt cortisol-mediating transcriptional regulation of related genes. Expert opinion: Patients with CS have limited treatment options; indeed, there is an unmet need for new compounds that target CYP11B1 selectively versus several steroidogenic enzymes and/or GR-signaling pathways. The complexity of steroid biosynthesis and signaling requires the application of structure-based drug discovery techniques that use molecular targets and highly similar off-targets. Significant differences in steroidogenesis between humans and other species necessitates caution over the choice of in vivo model for the preclinical evaluation of future potential compounds.