Sunday, May 4, 2025
5/4/2025
Steroid 11?-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 11ß-hydroxylase, encoded by the CYP11B1 gene, is the enzyme responsible for the last steps of cortisol production. Several medications are known to inhibit steroid 11ß-hydroxylase, but they also inhibit other cytochrome P450 enzymes, thus limiting their effectiveness and use for CS patients. Recent clinical trials with the potent steroid 11ß-hydroxylase inhibitor Osilodrostat (LCI699) have shown promise, but LCI699 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 CYP11B2), Angion has also identified compounds which potently inhibit the closely related CYP11B1. The present grant proposal aims for Angion to optimize this series of compounds for potency and selectivity towards CYP11B1 and thus identify truly selective steroid 11ß-hydroxylase inhibitors for use in CS patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).