Methods and compositions for treating glucocorticoid excess

Abstract

The disclosure provides a method of treatment for glucocorticoid excess in a patient in need thereof, comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor.

What is claimed is: 
     
         1 . A method of treatment for glucocorticoid excess in a patient in need thereof, comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor. 
     
     
         2 . The method of  claim 1 , further comprising the improvement or prevention of symptoms of glucocorticoid excess in the patient. 
     
     
         3 . The method of  claim 1 , further comprising reducing the levels of urinary tetrahydrocortisols in the patient, wherein the levels of the urinary tetrahydrocortisols are elevated compared to an asymptomatic patient. 
     
     
         4 . The method of  claim 1 , wherein the HSD-1 inhibitor is brain penetrant. 
     
     
         5 . The method of  claim 2 , wherein the symptoms of glucocorticoid excess comprise cardiovascular, metabolic, immunologic, osteal, muscular, dermatological, ocular, psychiatric, cognitive, circadian, or homeostatic symptoms. 
     
     
         6 . The method of  claim 5 , wherein:
 the cardiovascular symptoms are chosen from hypertension, atherosclerosis, endothelial dysfunction, prothrombic state, coronary artery disease, heart failure, and stroke;   the metabolic symptoms are chosen from obesity, glucose intolerance, insulin resistance, diabetes, and dyslipidemia;   the immunologic symptoms are chosen from infections and sepsis;   the osteal symptoms are chosen from osteoporosis, osteonecrosis, osteopenia, hypocalcemia, linear bone growth, and fractures;   the muscular symptoms are chosen from muscle atrophy and muscle weakness; or   the dermatological symptoms are chosen from impaired wound healing, thin or fragile skin, abnormal accumulations of subcutaneous fat, plethora, violaceous striae, acanthosis nigricans, hyperpigmentation, and easy bruisability;   the ocular symptoms are chosen from increased ocular pressure, glaucoma, exophthalmos, and cataract;   the psychiatric symptoms are chosen from depression, anxiety, hypomania, mania, and psychosis;   the cognitive symptoms are chosen from impairments in memory, visuospatial processing, reasoning, verbal learning, and language performance;   the circadian symptoms are chosen from insomnia, daytime fatigue, sleep apnea, fragmented sleep, increased nocturnal motor activity, and abnormal REM sleep; or   the homeostatic symptoms are chosen from hypokalemia, hypernatremia, hypophosphatemia, hypercalciuria, suppressed growth hormone, and thyroid disease.   
     
     
         7 . The method of  claim 1 , wherein the HSD-1 inhibitor does not show tachyphylaxis for human adipose HSD-1 inhibition. 
     
     
         8 . The method of  claim 1 , wherein the HSD-1 inhibitor is characterized by human pharmacokinetics consistent with target-mediated drug disposition. 
     
     
         9 . The method of  claim 8 , wherein plasma exposures of the HSD-1 inhibitor are less than dose-proportional after low single doses and dose-proportional after multiple low doses. 
     
     
         10 . The method of  claim 9 , wherein the doses are 10 mg or lower. 
     
     
         11 . The method of  claim 1 , wherein the HSD-1 inhibitor is characterized by human pharmacodynamics consistent with target-mediated drug-disposition. 
     
     
         12 . The method of  claim 11 , wherein the pharmacodynamic half-life of the HSD-1 inhibitor for hepatic HSD-1 inhibition is extended compared to its pharmacokinetic half-life. 
     
     
         13 . The method of  claim 12 , wherein the HSD-1 inhibitor has a pharmacodynamic half-life for human hepatic HSD-1 inhibition of at least 1 week. 
     
     
         14 . The method of  claim 1 , wherein the HSD-1 inhibitor is characterized by fast-on, slow-off binding kinetics to human HSD-1. 
     
     
         15 . The method of  claim 14 , wherein the residence time of the HSD-1 inhibitor is at least about 500 seconds. 
     
     
         16 . The method of  claim 1 , wherein the HSD-1 inhibitor forms hydrogen bonds to the pyrophosphate of NADPH in the human HSD-1 active site. 
     
     
         17 . The method of  claim 1 , wherein the HSD-1 inhibitor forms an aromatic stacking interaction with NADPH in the human HSD-1 active site. 
     
     
         18 . The method of  claim 1 , further comprising administration of a glucocorticoid medication to the patient. 
     
     
         19 . The method of  claim 18 , wherein the HSD-1 inhibitor is administered in a fixed-dose combination with the glucocorticoid medication. 
     
     
         20 . The method of  claim 18 , wherein the HSD-1 inhibitor and the glucocorticoid medication are co-packaged for separate administration. 
     
     
         21 . The method of  claim 18 , wherein the glucocorticoid medication is selected from prednisolone, methylprednisolone, dexamethasone, hydrocortisone, budesonide, deflazacort, beclomethasone, ciclesonide, fluticasone, mometasone, triamcinolone, flunisolide, clobetasol, betamethasone, fluocinonide, flurandrenolide, clocortolone, halobetasol, desoximetasone, desonide, halcinonide, prednicarbate, diflorasone, amcinonide, alclometasone, difluprednate, loteprednol, fluorometholone, rimexolone, and medrysone, or a pharmaceutically acceptable salt or ester derivatives thereof. 
     
     
         22 . The method of  claim 1 , wherein the patient has an ACTH- or CRH-secreting tumor. 
     
     
         23 . The method of  claim 1 , wherein the patient has a cortisol-secreting tumor. 
     
     
         24 . The method of  claim 1 , wherein the HSD-1 inhibitor is administered orally, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, ocularly, or topically. 
     
     
         25 . The method of  claim 1 , wherein the HSD-1 inhibitor has an estimated K d  lower than the K i . 
     
     
         26 . The method of  claim 25 , wherein the HSD-1 inhibitor has an estimated K d  at least about 60-fold lower than the K i . 
     
     
         27 . The method of  claim 1 , wherein the HSD-1 inhibitor has an estimated in vivo adipose IC 50  lower than that of the HSD-1 inhibitor measured in vitro. 
     
     
         28 . The method of  claim 27 , wherein the estimated in vivo adipose IC 50  is at least about 700-fold lower than measured in vitro. 
     
     
         29 . The method of  claim 1 , wherein the HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, MK-0736, MK-0916, BMS-823778, UE-2343, BI-187004, AMG-221, SAR-184841, Compound A, Compound B, Compound C, and Compound D, or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 29 , wherein the HSD-1 inhibitor is SPI-62, or a pharmaceutically acceptable salt thereof.