Steroid β hydroxylase inhibitor for Cushing s Syndrome

Cushing s Syndrome CS is caused by sustained elevated levels of cortisol Patients with CS often have high blood pressure abdominal obesity a round red face and are at an increased risk of morbidity especially related to cardiovascular disease CS can result from glucocorticoid medications that are used to treat inflammatory autoimmune and neoplastic disorders Other causes for CS are pituitary adenomas and adrenal tumors that lead to excessive cortisol production by the adrenal glands Treatment depends on the cause of CS but often involves pharmacological inhibition of cortisol production Steroid hydroxylase encoded by the CYP B gene is the enzyme responsible for the last steps of cortisol production Several medications are known to inhibit steroid hydroxylase but they also inhibit other cytochrome P enzymes thus limiting their effectiveness and use for CS patients Recent clinical trials with the potent steroid hydroxylase inhibitor Osilodrostat LCI have shown promise but LCI has poor selectivity and is in fact a more potent inhibitor of aldosterone production than of cortisol production As part of its successful medicinal chemistry program to identify potent and selective inhibitors of Aldosterone Synthase AS encoded by CYP B Angion has also identified compounds which potently inhibit the closely related CYP B The present grant proposal aims for Angion to optimize this series of compounds for potency and selectivity towards CYP B and thus identify truly selective steroid hydroxylase inhibitors for use in CS patients Cushing s Syndrome CS is caused by sustained elevated levels of cortisol in the body Depending on the cause treatment of CS can involve surgery or radiation However for many patients it involves pharmacological inhibition of cortisol production Steroid hydroxylase encoded by the CYP B gene is the enzyme responsible for the last steps of cortisol production Several medications are known to inhibit steroid hydroxylase but they also inhibit other cytochrome P enzymes thus limiting their effectiveness and use for CS patients None of the agents used at present were specifically designed for use in CS patients Angion has identified compounds which potently inhibit and the present grant proposal aims for Angion to optimize this series of compounds to identify truly selective steroid hydroxylase inhibitors for use in CS patients