Cushings 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 11?-hydroxylase, encoded by the CYP11B1 gene, is the enzyme responsible for the last steps of cortisol production. Several medications are known to inhibit steroid 11?-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 11?-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 11?-hydroxylase inhibitors for use in CS patients.
Public Health Relevance Statement: Cushings 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 11?-hydroxylase, encoded by the CYP11B1 gene, is the enzyme responsible for the last steps of cortisol production. Several medications are known to inhibit steroid 11?-hydroxylase, but they also inhibit other cytochrome P450 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 11?-hydroxylase inhibitors for use in CS patients.
Project Terms: Adrenal Gland Neoplasms; Adrenal Glands; Aldosterone; Aldosterone Antagonists; Animal Model; Applications Grants; associated symptom; Autoimmune Process; Blood Pressure; Cardiovascular Diseases; Central obesity; Clinical; Clinical Trials; Corticosterone; Corticotropin; Crystallization; Cushing Syndrome; CYP11B1 gene; CYP11B2 gene; CYP17A1 gene; CYP19A1 gene; CYP3A4 gene; Cytochrome P450; design; Development; Disease; Dose; drug efficacy; Drug Exposure; Drug Kinetics; Effectiveness; efficacy evaluation; efficacy study; efficacy testing; Electrolytes; Enzyme Inhibitor Drugs; Enzymes; Face; Future; Glucocorticoids; Goals; Homology Modeling; Hydrocortisone; Hypernatremia; Hypertension; Hypokalemia; in vivo; Inflammatory; inhibitor/antagonist; Lead; Measurement; Metyrapone; Mixed Function Oxygenases; Modeling; Morbidity - disease rate; mouse model; Mus; neoplastic; Operative Surgical Procedures; Oral; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Pituitary Gland Adenoma; Pre-Clinical Model; Production; programs; Property; Pump; Radiation; Risk; Safety; Series; Serum; small molecule inhibitor; Solid; Steroids; Structure; Testing; therapeutic evaluation; Toxicology; urinary; Weight Gain
