As the first in class steroid 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor, abiraterone acetate (of which the active metabolite is abiraterone) has been shown to improve overall survival in patients with castration-resistant prostate cancer (CRPC)--in those who are chemotherapy-naive and those previously treated with docetaxel. Furthermore, the clinical success of abiraterone demonstrated that CRPC, which has previously been regarded as an androgen-independent disease, is still driven, at least in part, by androgens. More importantly, abiraterone is a 'promiscuous' drug that interacts with a number of targets, which dictate its clinical benefits and adverse effects profile. Besides CYP17 inhibition, abiraterone acts as an antagonist to the androgen receptor and inhibits 3β-hydroxysteroid dehydrogenase--two effects that potentially contribute to its antitumour effects. However, the inhibition of the 17α-hydroxylase activity of CYP17, CYP11B1 and a panel of hepatic CYP enzymes leads to adverse effects and toxicities that include secondary mineralocorticoid excess. Abiraterone is also associated with increased incidence of cardiac disorders. Under such circumstances, development of new CYP17 inhibitors as an additional line of defence is urgently needed. To achieve enhanced clinical benefits, new strategies are being explored that include selective inhibition of the C17,20-lyase activity of CYP17 and multi-targeting strategies that affect androgen synthesis and signalling at different points. Some of these strategies-including the drugs orteronel, VT-464 and galeterone--are supported by preclinical data and are being explored in the clinic.

CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC(50) = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.

Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and volume, recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathological circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clinical trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.