Discovery of novel small molecule drugs for Cushing s disease

Project Summary Clinical signs of Cushingandapos s syndrome include growth of fat pads collarbone back of neck face trunk excessive sweating dilation of capillaries thinning of the skin muscle weakness hirsutism depression anxiety hypertension osteoporosis insulin resistance hyperglycemia heart disease and a range of other metabolic disturbances resulting in high morbidity If inadequately controlled in its severe forms Cushingandapos s syndrome is associated with high mortality The most common form of Cushingandapos s syndrome is Cushingandapos s disease due to microadenomas of pituitary corticotrophic cells that secrete excess ACTH First line therapy for Cushingandapos s disease is transphenoidal surgery to remove the pituitary tumor Medical therapy is required when surgery is delayed contraindicated or unsuccessful Adrenal enzyme inhibitors metyrapone ketoconazole prevent the synthesis of cortisol and can rapidly improve symptoms However metyropone is associated with hirsuitism in women because of the accumulation of androgenic steroids and patients must be monitored carefully to avoid hypoadrenalism Ketoconazole often requires progressively increasing dosage to maintain disease control but this is ultimately limited by the hepatotoxicity of the drug In addition it is a potent inhibitor of CYP A resulting in multiple drug interactions The recently approved somatostatin agonist pasireotide inhibits ACTH secretion but only of patients in a Phase III trial achieved normalization of urinary free cortisol while of patients experienced a hyperglycemia related adverse event due to the compoundandapos s potent inhibition of insulin secretion Therefore a significant unmet medical need exists for improved agents to treat Cushingandapos s disease Here we propose to develop a novel class of small molecule oral drugs to prevent excessive adrenal stimulation by ACTH These agents should normalize cortisol levels without the excess production of adrenal androgens or hepatotoxicity found with currently available adrenal enzyme inhibitors Design and screening of a focused chemical library resulted in a high hit rate and emerging structure activity relationships of a family of drug like starting points for medicinal chemistry Here we propose to use medicinal chemistry to explore this chemical series and establish necessary counter screens in order to demonstrate feasibility of this approach If successful an expanded medicinal chemistry effort in Phase II will result in a novel drug candidate for the treatment of Cushingandapos s disease ready for preclinical activities needed to begin clinical trials Project Narrative Cushingandapos s disease is a severe endocrine disorder with high morbidity and mortality Currently available medical therapy is poor If successful this project will result in a novel drug candidate for the treatment of Cushingandapos s disease with an improved safety and efficacy profile over existing therapeutic options