Melanocortin subtype-2 receptor (MC2R) antagonist for the treatment of ACTH-dependent Cushing's syndrome

Abstract

Methods and compositions for the treatment of ACTH-dependent Cushing's syndrome are provided herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 457,144, filed on April 5, 2023, which is incorporated herein by reference in its entirety.

[0002] This specification describes melanocortin subtype 2 receptor (MC2R) antagonists and methods of using MC2R antagonists in the treatment of ACTH-dependent Cushing's syndrome, which may result from a pituitary tumor (Cushing's disease) or an extrapituitary tumor (ectopic ACTH syndrome). [Background technology]

[0003] Melanocortin receptors form a family of G protein-coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R), which are selectively activated by different melanocortin peptides, adrenocorticotropic hormone (ACTH), and α-, β-, and γ-melanocyte-stimulating hormones (α-MSH, β-MSH, and γ-MSH), all of which derive from proteolytic activity from proopiomelanocortin hormone or POMC. ACTH is a major regulator of adrenal glucocorticoid synthesis and secretion and is a 39-amino acid peptide that has affinity only for MC2R. As a substance that plays a central role in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary gland in a circadian rhythm and in pulses in response to stress stimuli. ACTH acts in the adrenal glands to stimulate the synthesis and secretion of cortisol, which in turn regulates ACTH secretion through negative feedback in the hypothalamic-pituitary axis. In ACTH-dependent Cushing's syndrome, the pituitary gland and extrapituitary tumors secrete excessive ACTH without being controlled by the negative feedback that stimulates excessive cortisol secretion. Modulation of the MC2R is an attractive treatment for ACTH-dependent Cushing's syndrome. [Overview of the project]

[0004] A method for treating adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is disclosed herein.

[0005] In one embodiment, a method for treating adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in humans is disclosed herein, comprising orally administering about 80 mg to about 160 mg of a compound having the structure of compound 1, or a pharmaceutically acceptable salt thereof, once daily.

[0006] [ka]

[0007] In some embodiments, a person with ACTH-dependent Cushing's syndrome includes a pituitary adenoma.

[0008] In some embodiments, a person with ACTH-dependent Cushing's syndrome includes an ectopic ACTH-secreting tumor. In some embodiments, the ectopic ACTH-secreting tumor is located in the lung, pancreas, thyroid, thymus, intestine, adrenal gland, paraganglia, or a combination thereof.

[0009] In some embodiments, treating ACTH-dependent Cushing's syndrome includes lowering serum cortisol levels, lowering urinary cortisol levels, or both. In some embodiments, treating ACTH-dependent Cushing's syndrome includes lowering cortisol levels in humans by at least 10% from baseline.

[0010] In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing serum cortisol, androstenedione, or a combination thereof. In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing serum cortisol, androstenedione, or a combination thereof, by at least 10 from baseline.

[0011] In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof. In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof by at least 10% from baseline.

[0012] In some embodiments, treating ACTH-dependent Cushing's syndrome involves delaying or eliminating the need for removal of one or both adrenal glands.

[0013] In some embodiments, about 80 mg, about 120 mg, or about 160 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, about 80 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, about 120 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, about 160 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily in the evening.

[0014] A manufactured article is provided, comprising packaging material, compound 1 or a pharmaceutically acceptable salt thereof within the packaging material, and a label indicating that compound 1 or a pharmaceutically acceptable salt thereof is used to modulate the activity of melanocortin receptors (e.g., melanocortin subtype 2 receptors (MC2Rs)) or for the treatment, prevention, or improvement of one or more symptoms of a disease or condition that would benefit from the modulation of melanocortin receptor activity (e.g., melanocortin subtype 2 receptors (MC2Rs)), such as ACTH-dependent Cushing's syndrome.

[0015] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, various changes and modifications within the spirit and scope of this disclosure will become obvious to those skilled in the art from this detailed description, so please understand that the detailed description and specific examples, while illustrating specific embodiments, are given for illustrative purposes only. [Modes for carrying out the invention]

[0016] Adrenocorticotropic hormone (ACTH) is a 39-amino acid peptide synthesized by prepituitary cortical stimulant cells via proteolytic cleavage of proopiomelanocortin hormone (POMC). ACTH is a major regulator of the synthesis and secretion of adrenal glucocorticoids (GCs; cortisol in humans and most other species; corticosterone in rodents). As a central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted from the pituitary gland in response to stress stimuli and stimulates the synthesis and secretion of cortisol in the adrenal gland. This stimulation is mediated via a highly specific G protein-coupled receptor (GPCR) that is expressed almost uniquely in the adrenal cortex. The receptor is the melanocortin 2 receptor (MC2R), which, together with ACTH, is part of the larger melanocortin system.

[0017] The melanocortin system includes a family of five GPCRs (MC1R, MC2R, MC3R, MC4R, and MC5R), their natural agonists, melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormones (α-MSH, β-MSH, and γ-MSH), ACTH, and the endogenous melanocortin antagonist agouti and agouti-associated proteins (AGRP). Melanocortin receptors (MCRs) exhibit different selectivity for endogenous agonists and antagonist peptides, are expressed in diverse tissues, and perform diverse and modest physiological functions (Gantz, I. and TMFong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003).

[0018] It is possible to selectively modify any one or a combination of MCRs. In some embodiments, selective modification of any one or a combination of MCRs relative to other MCRs is useful in various clinical applications. In some embodiments, selective modification of any one or a combination of MCRs relative to other MCRs reduces undesirable side effects in various clinical applications. In one embodiment, the compounds described herein are antagonists of MC2R. In some embodiments, the compounds described herein are selective antagonists of MC2R compared to other MCRs.

[0019] MC2R is a highly selective receptor for ACTH. While ACTH can activate all five MCRs, at a physiological level, the sensitivity of the other receptors is not high enough to activate them, and ACTH selectively activates MC2R. Importantly, other naturally occurring agonists, α-MSH, β-MSH, and γ-MSH, do not have affinity for MC2R (Gantz, I. and TMFong, Am. J. Physiol. Endocrinol. Metab., 284:E468-E474, 2003). The main function of MC2R is to stimulate zona fasciculata cells in the adrenal cortex to synthesize and secrete cortisol. MC2R requires the normal secretion and function of the GPCR accessory protein MRAP (melanocortin 2 receptor protein) on the cell surface. MRAP is a small protein with a single transmembrane domain that forms an antiparallel homodimer in a stable complex with MC2R, and is required for both MC2R cell surface expression and the ability to bind to ACTH. MRAP can bind to any of the MCRs and affect their activity, but is essential only for MC2R activity. ACTH binding to the MC2R / MRAP complex on adrenal cortical cells is G S It activates to increase intracellular cAMP levels, and then stimulates cortisol synthesis and secretion by regulating several steps in the steroid production pathway.

[0020] Cushing's disease Cushing's syndrome (CS) is a set of clinical findings caused by prolonged exposure to excessive glucocorticoids. Clinical manifestations are highly diverse and may include muscle weakness, fatigue, bruising, weight gain, menstrual irregularities, and striae. Facial rounding, plethora, and marked fat deposition in the back and supraclavicular region are common. CS is associated with multiple cardiovascular, metabolic, skeletal, psychiatric, and dermatological comorbidities that significantly impair quality of life and functional status. Mortality is increased due to cardiovascular and infectious complications. These associated comorbidities and mortality rates can be reduced with early and effective treatment.

[0021] CS can be caused by excessive amounts of adrenocorticotropic hormone (ACTH) from either a pituitary tumor (referred to as Cushing's disease, CD) or a non-pituitary (i.e., ectopic) ACTH-secreting tumor (EAS). In these cases, the excessive cortisol production is induced by normal or elevated ACTH levels that are not suppressed by the negative feedback of cortisol. Alternatively, CS can be caused by exogenous glucocorticoids or an autonomous cortisol-secreting adrenal tumor. In these cases, the negative feedback effect of glucocorticoids on normal pituitary adrenocorticotropic hormone-producing cells leads to suppression of ACTH values. This difference in ACTH levels is used to distinguish between these two etiological mechanisms.

[0022] Surgical resection of the causative lesion is the optimal treatment for CS and may restore normal hypothalamic-pituitary-adrenal function. However, some patients cannot undergo surgery due to the risk or if the tumor is inoperable. In other patients, such as those with metastatic disease or invasive pituitary lesions, surgery will not be curative. Transsphenoidal surgery results in initial normalization of cortisol levels in 70% to 90% of patients in the hands of a specialized neurosurgeon, but the permanent cure rate is estimated to be 60% to 70%. Recurrence of CD has been reported months to decades after surgical outcomes that were initially thought to be curable. Primary pharmacological treatment is required for all of these patients, and adjuvant treatment is required for CD patients who are receiving radiation until the tumor is controlled.

[0023] Regardless of the cause of CS, current medical treatments for it can be directed at the adrenal glands via inhibition of enzymes leading to cortisol synthesis (osilodrostat, ketoconazole, levoketoconazole, metyrapone, and etomidate), or can be directed at the glucocorticoid receptor (to antagonize glucocorticoid action: mifepristone). Therapies for CD also include agents that inhibit ACTH secretion: cabergoline and pasireotide. These agents are associated with toxicities that can prevent their long-term use at effective doses (e.g., hypogonadism in men or abnormal liver function in patients taking ketoconazole), and the need for multiple agents to treat severe hypercortisolism increases the risk of adverse events.

[0024] In healthy individuals and those with ACTH-dependent CS, ACTH acts on the adrenal glands, stimulating the synthesis and secretion of cortisol through activation of MC2R. Cortisol is the body's main stress hormone, and excessive amounts can cause a significant increase in mortality and morbidity. Corticotroph adenomas are small, usually slow-growing, benign tumors that are typically clinically noted as a result of the effects of glucocorticoid excess. CD is commonly seen in women and usually develops between the ages of 30 and 50. CD often takes many years to diagnose, with an estimated diagnostic time of 38 months, and many of its symptoms such as somnolence, depression, obesity, hypertension, hirsutism, and menstrual irregularities can be wrongly attributed to other more common diseases, so it can be significantly underdiagnosed in the general population.

[0025] The first-line therapy for ACTH-dependent CS is surgical, involving the removal of either an ACTH-secreting pituitary tumor or, in severe cases, the adrenal gland itself. Because surgery is often unsuccessful, contraindicated, or delayed, pharmacological treatment is necessary for these patients. Adrenal enzyme inhibitors (e.g., metyrapone and ketoconazole) can prevent cortisol synthesis and improve symptoms, but they have side effects due to their mechanism of action. For example, metyrapone is associated with hirsutism in women, and patients must be carefully monitored to avoid adrenal insufficiency, hypokalemia, and hypertension. Ketoconazole often requires incremental dose increases to maintain disease control, which is ultimately limited by the drug's hepatotoxicity. In addition, ketoconazole is a potent inhibitor of CYP3A4, one of the most important drug-metabolizing enzymes in the liver, and has the potential for negative drug interactions as a side effect. Mifepristone, a potent glucocorticoid receptor antagonist, is approved for controlling hyperglycemia in Cushing's syndrome, but it is difficult to titrate and has serious side effects due to its potent anti-progesterone activity.

[0026] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is used to treat Cushing's syndrome. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is used to treat ACTH-dependent Cushing's syndrome. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is used to treat Cushing's disease.

[0027] compound 1 Compound 1 refers to 6-(2-ethoxyphenyl)-3-((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutan-1-carbonyl)piperazine-1-yl)-N-((S)-quinuclidin-3-yl)picolinamide, which has the following chemical structure.

[0028] [ka]

[0029] Compound 1 is also known as N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazine-1-yl]pyridine-2-carboxamide.

[0030] Preclinical trials Compound 1 exhibits more than 2900 times greater selectivity than other human melanocortin receptor subtypes and is a potent oral, non-peptide, small molecular weight MC2R antagonist (K i Compound 1 is <10 nM. Compound 1 potently blocked ACTH binding to the receptor, ACTH-mediated G protein activation, and subsequent cAMP production. In screening for potential off-target activities, compound 1 showed strong blocking of 5-HT 1B It has weak antagonist activity against the receptor and no agonist activity, and 5-HT 1B It exhibited more than 2200 times greater selectivity for hMC2R.

[0031] In in vitro studies, the metabolism of compound 1 in 9000g supernatant fractions of plasma, liver microsomes, and / or liver homogenate (liver S9) from various species (including humans) was evaluated. The main metabolic pathway known to be involved in the metabolic clearance of compound 1 is oxidative metabolism, leading to hydroxylation and the formation of desmethyl metabolites. CYP3A4 plays a significant role in catalyzing these reactions, and CYP2D6 and CYP2C8 may also have small contributions. CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 were not involved.

[0032] Oral administration of compound 1 dose-dependently suppressed corticosterone (equivalent to human cortisol in mice) secretion in male and female rats after 1 μg / kg ACTH (1-24) at doses of 3 and 10 mg / kg. Dose-dependent suppression of corticosterone was observed only at 1 hour and 4 hours after ACTH administration at 1, 4, 24, and 48 hours after a single dose of compound 1.

[0033] Disease models mimicking ACTH excess and hypercortisolosis included rats administered exogenous ACTH (1-24) via subcutaneous osmotic pumps over 7 days, and mice transplanted with ACTH-secreting corticotroph AtT-20 tumor cells. Animals received either placebo or oral administration of compound 1 daily. In each model, corticosterone levels on days 1 and 7 showed a significant dose-dependent decrease of up to 92%, accompanied by dose-dependent adrenal atrophy. Compound 1 also reduced ACTH-stimulated aldosterone levels but did not affect angiotensin-II stimulation of aldosterone, which accounts for most aldosterone production. However, 6 days after discontinuation of the highest dose of compound 1 (75 mg / kg for 15 days), Ang-II-stimulated aldosterone was suppressed, but sodium and potassium levels remained normal.

[0034] The overall nonclinical safety of compound 1 was evaluated in 28-day and 3-month repeated-dose general toxicity studies in rats and dogs, as well as in a series of in vitro and in vivo genotoxicity and safety pharmacology studies. Repeated-dose toxicity studies demonstrated and further evaluated effects in the lungs of rats and the adrenal glands and livers of dogs. Target organs of toxicity identified in repeated-dose toxicity studies included (1) foamy macrophages in the lungs in the 28-day rat study, and (2) adrenal and hepatic atrophy in the dog study. Findings in the rat lungs were confirmed to be inconsistent with drug-induced PLD. Findings in the adrenal glands and livers of dogs were shown to be alleviated by hydrocortisone supplementation, demonstrating that these findings are extensions of pharmacology. No findings indicating significant genotoxic risk or adverse effects on core organ systems, including the cardiovascular, central nervous system, and respiratory system, were observed.

[0035] Treatment method In certain embodiments, methods for treating ACTH-dependent Cushing's syndrome (CS) in subjects are disclosed herein. ACTH-dependent Cushing's syndrome includes Cushing's disease (CD) and ectopic ACTH syndrome (EAS). In some embodiments, the treatment includes reducing cortisol levels. In some embodiments, the treatment includes reducing endogenous ACTH-induced cortisol levels. In some embodiments, the subjects are human.

[0036] In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing cortisol levels in humans. In some embodiments, the method involves reducing endogenous cortisol levels. In some embodiments, endogenous cortisol levels are reduced in blood, serum, saliva, or urine. In some embodiments, the method involves reducing cortisol. In some embodiments, cortisol levels are reduced in blood, serum, saliva, or urine. In some embodiments, blood cortisol levels are reduced. In some embodiments, serum cortisol levels are reduced. In some embodiments, treating ACTH-dependent Cushing's syndrome involves lowering serum cortisol levels, lowering urinary cortisol levels, or both. In some embodiments, salivary cortisol levels are reduced. In some embodiments, urinary free cortisol (UFC) levels are reduced. In some embodiments, cortisol secretory capacity is reduced as determined by an ACTH stimulation test. In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing cortisol levels in humans by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing cortisol levels in blood, saliva, or urine by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing cortisol levels in blood, urine, or both by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline.In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing blood cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing serum cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing salivary cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing urine cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, the cortisol level is reduced compared to the cortisol level before treatment. In some embodiments, cortisol levels are reduced to those of a person not having one of the diseases described herein. That is, in some embodiments, cortisol levels are restored to normal levels in a person.

[0037] In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing at least one level of: serum cortisol, androstenedione, or a combination thereof in a subject. In some embodiments, treating ACTH-dependent Cushing's syndrome includes lowering the levels of serum cortisol, androstenedione, or a combination thereof. In some embodiments, the level of serum cortisol or androstenedione is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome includes lowering the levels of serum cortisol, androstenedione, or a combination thereof by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline.

[0038] In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof. In some embodiments, the level of any one of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), or dehydroepiandrosterone (DHEA) is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some embodiments, treating ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof, from baseline by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30%.

[0039] In some embodiments, treating ACTH-dependent Cushing's syndrome includes treating one or more symptoms of Cushing's syndrome. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing fat pad growth (clavicular, back of neck, face, and torso), excessive sweating, telangiectasia, skin thinning, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity (including trunk obesity, abdominal obesity, and central obesity), menstrual irregularities, or a combination thereof. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing fat pad growth (clavicular, back of neck, and face). In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing excessive sweating. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing telangiectasia. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing skin thinning. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing muscle weakness. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing hirsutism. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing depression / anxiety. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing hypertension. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing the risk of osteopenia, osteoporosis, or fracture. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing insulin resistance, the risk of hyperglycemia, diabetes, or the need for glucose-lowering drugs. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing hypertension or the need for blood pressure-lowering drugs.

[0040] In some embodiments, treating EAS includes reducing the risk of blood potassium abnormalities or thrombosis.

[0041] In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing hyperglycemia. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing heart disease. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing lethargy. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing obesity. In some embodiments, treating ACTH-dependent Cushing's syndrome includes reducing menstrual irregularities, infertility, hirsutism, acne, or androgen-driven alopecia in women.

[0042] In some embodiments, treating ACTH-dependent Cushing's syndrome involves delaying or eliminating the need for removal of one or both adrenal glands.

[0043] subject In some embodiments, the subject is human. In some embodiments, the subject has a disease associated with excessive ACTH. In some embodiments, the subject has ACTH-dependent Cushing's syndrome.

[0044] In some embodiments, a person with ACTH-dependent Cushing's syndrome has at least two of the following: (i) serum cortisol is not suppressed to less than 1.8 μg / dL during a 1 mg dexamethasone suppression test (DST); (ii) bedtime salivary cortisol levels exceed ULN for at least four consecutive times (each value obtained at intervals of approximately 7 to 14 days); and (iii) 24-hour urinary free cortisol (UFC) levels exceed 1.3 × ULN and not lower for at least four consecutive times (each value obtained at intervals of approximately 7 to 14 days).

[0045] In some embodiments, humans have elevated serum cortisol levels in low-dose dexamethasone suppression studies. In some embodiments, humans have serum cortisol levels of 1.8 mcg / dL or higher the morning after nocturnal administration of 1 mg of dexamethasone.

[0046] In some embodiments, humans have nocturnal salivary cortisol levels higher than the human ULN. In some embodiments, humans have nocturnal salivary cortisol levels at least 1.5 times, 2.0 times, 2.5 times, or more than the ULN. In some embodiments, the ULN for nocturnal salivary cortisol levels is about 100 ng / dL.

[0047] In some embodiments, humans have a 24-hour urinary free cortisol (UFC) level higher than the human ULN. In some embodiments, humans have a 24-hour UFC at least 1.3 times the ULN. In some embodiments, humans have a 24-hour UFC at at least 1.5 times, 2.0 times, 2.5 times, or more than the ULN. In some embodiments, humans have a 24-hour UFC that is about 50 mcg / day, 100 mcg / day, 150 mcg / day, 200 mcg / day, or more high in a 24-hour urinary cortisol test. In some embodiments, the ULN for 24-hour urinary cortisol excretion is about 50–55 mcg / day.

[0048] In some embodiments, ACTH-dependent Cushing's syndrome includes: (a) nocturnal serum cortisol > 7.5 μg / dL, or bedtime salivary cortisol > ULN (cortisol levels are measured before initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof); and (b) early morning plasma ACTH > 10 pg / mL (plasma ACTH is measured before initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof).

[0049] In some embodiments, a person with ACTH-dependent Cushing's syndrome has a pituitary tumor (pituitary adenoma) or a corticotrov adenoma. In some embodiments, a person with ACTH-dependent Cushing's syndrome has a pituitary tumor (pituitary adenoma). In some embodiments, a person with ACTH-dependent Cushing's syndrome has a corticotrov adenoma. In some embodiments, the pituitary adenoma or corticotrov adenoma is benign. In some embodiments, treating ACTH-dependent Cushing's syndrome includes treating the corticotrov adenoma.

[0050] In other embodiments, humans have ectopic ACTH-secreting tumors. In some embodiments, humans have ACTH-secreting tumors in organs that do not normally produce ACTH. In some embodiments, the ACTH-secreting tumors are located in the lungs, pancreas, thyroid gland, thymus, intestines, adrenal glands, paraganglia, or a combination thereof. In some embodiments, the ACTH-secreting tumors are malignant. In some embodiments, the ACTH-secreting tumors are benign.

[0051] Dosage and administration In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the treatment of ACTH-dependent Cushing's syndrome. A method for providing such treatment to a subject in need of treatment for ACTH-dependent Cushing's syndrome includes administering to the subject a therapeutically effective dose of a pharmaceutical composition comprising at least compound 1 or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally to humans. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to humans in a continuous dosing schedule. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to humans in a continuous daily dosing schedule.

[0053] The term "continuous dosing schedule" refers to regular administration. In some embodiments, a continuous dosing schedule refers to regular administration of a particular therapeutic agent without any breaks in treatment.

[0054] The term "continuous daily dosing schedule" refers to administering a specific therapeutic agent at approximately the same time each day. In some embodiments, the daily dosing is once a day.

[0055] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily in the evening.

[0056] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 50 mg to about 200 mg of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg to about 160 mg of compound 1.

[0057] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg, 120 mg, or 160 mg of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 120 mg of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 160 mg of compound 1.

[0058] In certain cases, it is appropriate to administer at least one additional therapeutic agent in combination with compound 1 or a pharmaceutically acceptable salt thereof.

[0059] Adrenal glucocorticoid "block and replace" therapy In one particular embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered co-administered with one or more additional therapeutic agents, the one or more of which are selected from glucocorticoids, mineralocorticoids, or combinations thereof. In some embodiments, the administration of compound 1 or a pharmaceutically acceptable salt thereof includes reducing the exogenous glucocorticoid dose requirement for humans. Examples of glucocorticoids intended for co-administration include, but are not limited to, beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, etamethasoneb, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and the like. Examples of mineralocorticoids intended for co-administration include, but are not limited to, fludrocortisone.

[0060] In some embodiments of the treatment of ACTH-dependent Cushing's syndrome, compound 1 or a pharmaceutically acceptable salt thereof is administered co-administered with a second therapeutic agent, the second therapeutic agent being a glucocorticoid (i.e., “block replacement” therapy). In some embodiments, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, etametazoneb, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone. In some embodiments of the treatment of ACTH-dependent Cushing's syndrome, compound 1 or a pharmaceutically acceptable salt thereof is administered co-administered with a low dose of glucocorticoid. In some embodiments, the low dose of glucocorticoid contains a cortisone equivalent of 20 mg / day or less. In some embodiments, the low dose of glucocorticoid contains a cortisone equivalent of 15 mg / day or less. In some embodiments, the low dose of glucocorticoid contains a cortisone equivalent of 10 mg / day or less. In some embodiments, the low-dose glucocorticoid contains a cortisone equivalent of 5 mg / day or less.

[0061] In some embodiments of the treatment of ACTH-dependent Cushing's syndrome, the method further comprises administering adrenal glucocorticoid replacement therapy when serum cortisol is less than 5 μg / dL, and serum cortisol is measured in the early morning. In some embodiments, early morning is approximately 05:30 to 08:00. In some embodiments, the adrenal glucocorticoid replacement therapy includes hydrocortisone. In some embodiments, hydrocortisone is administered in a physiological hydrocortisone replacement dose. In some embodiments, hydrocortisone is administered in a hyperphysiological hydrocortisone replacement dose.

[0062] In some embodiments of the treatment of ACTH-dependent Cushing's syndrome, the method further includes the administration of mineralocorticoid replacement therapy. In some embodiments, the mineralocorticoid replacement therapy includes fludrocortisone.

[0063] Pharmaceutical composition In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the treatment of the active compound into a preparation for pharmaceutical use. The appropriate formulation depends on the selected route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0064] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as separate units, such as capsules or tablets, containing a predetermined amount of compound 1 or a pharmaceutically acceptable salt thereof, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

[0065] Specific terms Unless otherwise specified, the following terms used in this application have the definitions set forth below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limited. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein.

[0066] As used herein and in the claims, the singular forms "a," "an," and "the" include plural references unless otherwise clearly indicated by the context. For example, the term "sample" includes multiple samples, including mixtures thereof.

[0067] As used herein, the term “approximately” refers to a range of plus or minus 10% of that number. The term “approximately” range refers to the range minus 10% of its minimum value and plus 10% of its maximum value.

[0068] The terms “determining,” “measuring,” “evaluating,” “assessing,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present or not (e.g., detection). These terms may include quantitative, qualitative, or quantitative and qualitative determinations. Evaluations may be relative or absolute. “Detecting the presence of” may, depending on the context, include determining the quantity of something that is present, in addition to determining whether it is present or not.

[0069] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not cause any lasting adverse effect on the general health of the subject being treated.

[0070] As used herein, the term “modulate” means to interact with a target, either directly or indirectly, in such a way as to alter the activity of the target, including, but not limited to, enhancing, inhibiting, limiting, or prolonging the activity of the target.

[0071] As used herein, the term “modulator” refers to a molecule that interacts with a target, either directly or indirectly. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0072] The terms “administer,” “give delivery,” and “dosage,” as used herein, refer to methods that may be used to enable the delivery of a compound or composition to a desired site of action. These methods include, but are not limited to, oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art will be familiar with the administration techniques that may be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0073] When used herein, terms such as "simultaneous administration" mean the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the drugs are administered by the same or different routes of administration or at the same or different times.

[0074] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an agent or compound administered that alleviates, to some extent, one or more of the symptoms of the disease or condition being treated. The results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is necessary to produce a clinically significant reduction in the symptoms of the disease. The appropriate “effective” dose in any individual case is, at the discretion of the user, determined using techniques such as dose-escalation studies.

[0075] As used herein, the term “pharmaceutical combination” means a product resulting from a mixture or combination of two or more active ingredients, and includes both immobilized and unimmobilized combinations of active ingredients. The term “immobilized combination” means that both the active ingredient, e.g., compound 1 or a pharmaceutically acceptable salt thereof, and the concomitant drug are administered to the patient simultaneously in the form of a single entity or preparation. The term “unimmobilized combination” means that the active ingredient, e.g., compound 1 or a pharmaceutically acceptable salt thereof, and the concomitant drug are administered to the patient as separate entities simultaneously, concurrently, or successively without specific intervening time limitations, and such administration results in effective levels of the two compounds in the patient’s body. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0076] The terms "product" and "kit" are used as synonyms.

[0077] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, humans, non-human primates such as chimpanzees, and other apes and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; farm animals such as rabbits, dogs, and cats; and laboratory animals such as rodents such as rats, mice, and guinea pigs. In one embodiment, a mammal is a human.

[0078] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, reducing, or improving at least one symptom of a disease or condition; preventing additional symptoms; inhibiting a disease or condition, for example, preventing the progression of a disease or condition; reducing a disease or condition; causing regression of a disease or condition; reducing a condition caused by a disease or condition; or stopping the symptoms of a disease or condition, either prophylactically and / or therapeutically.

[0079] Throughout this application, various embodiments may be presented in range form. It should be understood that range form descriptions are merely for convenience and conciseness and should not be interpreted as a rigid limitation to the scope of this disclosure. Therefore, range descriptions should be considered to specifically disclose not only the individual numbers within that range but also all possible subranges. For example, a range description such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0080] The section headings used herein are for organizational purposes only and should not be construed as limiting the subjects described. [Examples]

[0081] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0082] Example 1: Phase 1b / 2a open-label multiple-ascending dose exploratory study of compound 1 in ACTH-dependent Cushing's syndrome. Non-limiting examples of clinical trials of ACTH antagonists in humans are listed below.

[0083] Research Description This is a Phase 1b / 2a, first-in-disease, open-label, uncontrolled, repeated dose-escalation exploratory study to evaluate the safety, tolerability, and pharmacokinetics (PK) of compound 1 in participants with ACTH-dependent Cushing's syndrome (Cushing's disease or ectopic ACTH syndrome).

[0084] The study requires a 14-day hospital stay during which participants will receive oral compound 1 once daily for 10 days, followed by a 4-day "washout" period during which they will be monitored. Vital signs and safety laboratory values ​​will be collected.

[0085] the purpose The primary objectives are to evaluate the safety and tolerability of compound 1 in participants with ACTH-dependent Cushing's syndrome, and to evaluate the pharmacokinetics of compound 1 in participants with ACTH-dependent Cushing's syndrome.

[0086] Secondary objective: To record changes in serum cortisol levels in the early morning (approximately 05:30-08:00).

[0087] The exploratory objective is to demonstrate a reduction in urinary free cortisol (UFC) in participants with ACTH-dependent Cushing's syndrome. It also aims to evaluate the effects of compound 1 on ACTH, other adrenal steroids, clinical characteristics, and biochemistry.

[0088] Evaluation items Primary endpoint: Evaluation of the safety and tolerability of compound 1 in participants with ACTH-dependent Cushing's syndrome: • Daily assessment of adrenal insufficiency through early morning serum cortisol levels, adrenal insufficiency questionnaire, and in-person visits. Measurement of CBC (including white blood cell count), electrolytes, BUN, glucose, creatinine, and liver function tests. • Measurement of insulin and pituitary function tests before and after treatment. • Daily ECG evaluation · Aldosterone and renin activity

[0089] Pharmacokinetic evaluation items: · Maximum plasma concentration (C max ) · Time (t max to max ) · Area under the plasma concentration-time curve (AUC 0-24 ) · Accumulation index of C<0​​​​​​​​​​​​​​​​​​​​​​​​​​• Diastolic blood pressure (mmHg) • Weight (kg) and waist circumference (cm)

[0093] Research group: Up to 40 participants, aged 18–75 years at screening, with a confirmed diagnosis of active ACTH-dependent Cushing's syndrome (Cushing's disease or ectopic ACTH syndrome), to achieve 6 completers for each dose cohort.

[0094] Study patient eligibility criteria: To participate in this study, participants must have active ACTH-dependent Cushing's syndrome. Participants may be under the care of the research team, awaiting surgery or radiotherapy, or have undergone surgery and / or are awaiting a response to radiotherapy. Participants who do not meet the remission criteria within 5 days after resection of a potentially ACTH-producing tumor should not begin screening until 6 weeks after the date of surgery. Alternatively, they may be hospitalized for evaluation of the cause of Cushing's syndrome.

[0095] To be eligible to participate in this study, an individual must meet all of the following criteria: provide a signed and dated informed consent form; be able to understand and sign the informed consent document; be willing to abide by all research procedures and interventions; be able to take oral medications; be a male or female between the ages of 18 and 75; have received a COVID-19 vaccination in accordance with current CDC recommendations; and have evidence supporting a diagnosis of Cushing's syndrome, defined as meeting two of the following three criteria, administered within 56 days prior to day 1: (i) serum cortisol levels are not suppressed to less than 1.8 μg / dL during a 1 mg dexamethasone suppression test (DST) with an oral estrogen-containing drug. It may be used in all participants except women taking medication, (ii) bedtime salivary cortisol levels exceeding ULN for at least four consecutive times (at intervals of 7 to 14 days), and (iii) 24-hour urinary free cortisol (UFC) levels exceeding 1.3 × ULN for at least four consecutive times (at intervals of 7 to 14 days) without any lower values ​​(however, for participants previously diagnosed with ACTH-dependent Cushing's syndrome who are awaiting surgery or radiotherapy, or who have had a failed surgery or are awaiting the effects of radiotherapy, DST is not required, and only one additional UFC or bedtime salivary cortisol elevation within three weeks on day 1 is required). Evidence of “active” ACTH-dependent Cushing’s syndrome within 14 days of day 1 is defined as follows: (i) nocturnal (approximately 23:00-00:00) serum cortisol > 7.5 μg / dL or bedtime salivary cortisol > ULN, and (ii) early morning (approximately 05:30-08:00) plasma ACTH > 10 pg / mL. Participants who are taking a short-acting steroid production inhibitor (ketoconazole, levoketoconazole, oscilodrostat, cabergoline, or metyrapone) and who have documented ACTH-dependent Cushing’s syndrome may participate after a 14-day washout period if they meet the other eligibility criteria.

[0096] Exclusion criteria: Individuals meeting any of the following criteria will be excluded from participation in this study: pregnant or breastfeeding women; a history of bilateral adrenalectomy; a history of adrenal insufficiency when taking compound 1 in this study; a history of pituitary MRI findings of lesions within 3 mm of the optic chiasm; the presence of any known malignancy; ULN with a UFC of 5x or higher; use of mitotane; use of prohibited or non-prescription drugs and / or non-drug / alternative medications within 7 days prior to screening and unwillingness to discontinue the use of these substances during the study; use of a drug that is a strong inducer of cytochrome (CYP) 3A4 within 30 days prior to enrollment; use of a drug that is a strong or moderate inhibitor of CYP3A4 or intake of food within 14 days prior to enrollment; use of a drug that is a strong or moderate inducer of P-gp within 14 days prior to the first dose of the study drug; use of a drug that is a strong or moderate inhibitor of P-gp within 14 days prior to the first dose of the study drug; or within the past 30 days or 5.5 days prior to the date of administration of compound 1. Use of the study drug during the longer of the two periods, any condition that, in the opinion of the principal investigator, could jeopardize the participant's appropriate participation in this study, a history of unsuccessful surgery for Cushing's syndrome within the past six weeks, and any abnormal baseline electrocardiogram in any of the following ways: (a) QTcF >500 milliseconds (or >530 milliseconds for participants with bundle branch block) repeated in a second set of ECGs at least two hours apart, based on the mean of three ECGs; (b) any ventricular tachycardia associated with symptoms of hemodynamic response; (c) sustained ventricular tachycardia (lasting longer than 30 seconds), regardless of symptoms; (d) torsades de pointe; (e) cardiac arrest; (f) pauses longer than 5 seconds; (g) type II second-degree block or third-degree atrioventricular block; (h) clinically significant symptomatic bradycardia; (i) any supraventricular tachycardia associated with symptoms of hemodynamic response.

[0097] Lifestyle considerations: During this study, participants will be asked to: refrain from consuming Seville oranges, grapefruit, pomelo, exotic citrus fruits, grapefruit hybrids, or juices containing any of these fruits in quantities of 8 ounces or more, from 7 days before the first dose of Compound 1 until after the final dose; refrain from consuming red wine from 2 days before the first dose of Compound 1 until after the final dose; participants who use tobacco products will be instructed not to use nicotine-containing products within the clinical center; and refrain from strenuous exercise during the study period.

[0098] Overall research design This is a single-center, Phase 1b / 2a, disease-initial, open-label, uncontrolled, repeated dose-escalation exploratory study to evaluate the safety, tolerability, pharmacokinetic, and efficacy signals of compound 1 (ACTH receptor antagonist) in participants with active ACTH-dependent Cushing's syndrome.

[0099] Six participants will be placed in each dose cohort to ensure continuous availability. Participants may be placed in more than one dose cohort. The study requires a 14-day hospital stay during which participants will receive oral compound 1 once daily for 10 days, followed by a 4-day "washout" period during which they will be monitored. Vital signs and safety laboratory values ​​will be obtained on a separate day. Blood cortisol levels and 24-hour UFC will be the primary measures of efficacy signaling. There will be one safety follow-up review between days 24 and 31.

[0100] Dosage justification The starting dose of 80 mg is based on available toxicity and clinical data from studies in healthy volunteers. At lower doses, adequate control of serum and urinary cortisol is unlikely in participants with Cushing's syndrome, where basal ACTH and cortisol levels are significantly higher than those seen in healthy volunteers. The proposed maximum daily dose is 160 mg. Based on population PK models, this dose corresponds to mean steady-state C levels of 2510 ng / mL and 31,800 ng × h / mL, respectively. max and AUC 0-24It is predicted that it will have the following characteristics. Histopathological findings observed in repeated-dose toxicity studies in rats and dogs (i.e., lungs, adrenal glands, and liver) typically occur only after repeated dose administration, with peak exposure (C max It is more likely to correlate with total exposure (AUC) rather than with the individual compound. Therefore, compound 1 is expected to be safely administered to healthy participants with ACTH-dependent Cushing's syndrome at a planned dose of up to 160 mg.

[0101] intervention: Compound 1 will be administered as an oral tablet once daily for 10 days. Three dose-escalating cohorts are expected: 80, 120, and 160 mg per day. The first cohort will receive a dose of 80 mg. Subsequent cohorts may receive 120 mg and 160 mg. Participation period: within 45 days.

[0102] A sequential, open-label, 10-day fixed-dose cohort of six participants: Cohort 1: Compound 1 80 mg, once daily Cohort 2: Compound 1 120 mg, once daily Cohort 3: Compound 1 160 mg, once daily

[0103] Participants will receive compound 1 once daily for 10 days at approximately 8:00 a.m., in a dose appropriate for the cohort. The tablet will be taken orally with 240 mL of water. The drug may be taken before or after breakfast, as it has minimal impact on food absorption.

[0104] Glucocorticoid deficiency Glucocorticoid deficiency is a notable adverse event (AESI) that may result from the pharmacological effects of compound 1. Glucocorticoid deficiency is treated with glucocorticoid replacement therapy at a dose determined by the principal investigator. Mild to moderate glucocorticoid deficiency will not warrant modification of the study drug, in the opinion of the principal investigator, as long as there is a rapid clinical response to any relevant symptoms or signs in response to glucocorticoid therapy.

[0105] Consistent with the pharmacological effects of the study drug, glucocorticoid deficiency was observed during treatment with compound 1 in previous studies involving healthy volunteers. Therefore, in this study, glucocorticoid deficiency is identified as an AESI and may lead to dose-limiting toxicity.

[0106] Mild to moderate glucocorticoid deficiency is defined as inadequately low basal or ACTH-stimulated serum cortisol levels, with or without concomitant related symptoms or signs (e.g., nausea, loss of appetite, hyponatremia). Initiation of HC therapy is recommended for all participants with early morning (approximately 05:30-08:00) serum cortisol <5 μg / dL, regardless of symptoms.

[0107] Severe (hypotensive) glucocorticoid deficiency is defined as an acute deterioration of a healthy state, including but not limited to the above signs and symptoms associated with absolute hypotension (systolic blood pressure < 100 mm Hg) or relative hypotension (systolic blood pressure ≥ 20 mm Hg (lower than normal)), characterized by resolution within 1 to 2 hours after parenteral HC administration (i.e., marked resolution of hypotension within 1 hour and improvement of clinical symptoms over a 2-hour period).

[0108] Participants diagnosed with glucocorticoid deficiency will receive hydrocortisone (and other potential interventions) depending on the severity of their condition. The diagnosis and management of glucocorticoid deficiency and the supervision of hydrocortisone therapy will be overseen by the principal investigator, and participants will receive treatment in accordance with standard care.

[0109] Before initiating HC therapy, if possible, blood should be collected for measurement of serum cortisol, ACTH, aldosterone, renin activity, chemistry (sodium, potassium, glucose), and scheduled hormone measurements.

[0110] For asymptomatic or mildly symptomatic participants, HC should be administered at a physiological HC alternative dose.

[0111] If any of the following scenarios occur, administration of the study drug may be continued under careful monitoring: (1) the participant is asymptomatic and has physiological HC replacement, or (2) any symptoms or signs associated with mild to moderate glucocorticoid deficiency, as determined by the principal investigator, respond rapidly to glucocorticoid treatment.

[0112] Screening procedure Cushing's syndrome is diagnosed in patients who were diagnosed with Cushing's syndrome 56 days prior to registration, based on the results of a 1 mg dexamethasone suppression test, four or more elevated bedtime salivary cortisol levels, and / or four or more elevated UFC levels exceeding 1.3 times the normal level, or one elevated UFC or salivary cortisol level within the past 21 days.

[0113] Participants with active Cushing's syndrome will undergo the following screening activities only after signing the consent form for this study: pregnancy test, triple 12-lead ECG, and measurement of electrolytes, glucose, blood urea nitrogen, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transferase (GGT), complete blood count, nocturnal serum cortisol, pituitary MRI, and morning plasma ACTH.

[0114] Research evaluation and procedures The study requires the collection of biological samples before, during, and after administration of research drug compound 1 for 10 days.

[0115] The physical examination includes measuring height, weight, waist circumference, and vital signs (blood pressure, pulse, temperature, respiratory rate) using autonomic pulsation and BP measurement with the correct cuff size; evaluation of thyroid, heart, and lung sounds; abdominal sounds, tenderness, organ size, presence of abnormal fat (dorsocervical, supraclavicular, temporal) depots or significant central fat; presence of acne; hirsutism, streaks or pigmentation; muscle strength; and a mini-psychological examination. BMI is calculated once during the examination on the first day.

[0116] Participants will be instructed on how to complete an online questionnaire regarding symptoms of adrenal insufficiency. Participants will also complete a Cushing's syndrome questionnaire. The questionnaire asks participants, "To what extent have you experienced any of the following symptoms in the past few days? For each symptom, please select the answer that best describes your experience." Symptoms include brain fog, difficulty concentrating, sleep disturbances, edema or bloating, anxiety, depression, and irritability. The answers are "not at all, slightly, moderate, very, extremely."

[0117] Biological sample evaluation Screening, safety, and efficacy measurements include CBC (including white blood cell count), liver panel, GGT, ACTH, cortisol, androstenedione, 11-oxyandrogens (11KT and 11OHΔ4A), 17-OH progesterone, dehydroepiandrosterone (DHEA), progesterone, testosterone, prolactin, IGF-1, growth hormone, acute care panel, POMC-related peptide, frustrationamine, insulin, LH, FSH, testosterone (male), estradiol (female), renin activity, aldosterone, and pharmacokinetics of compound 1.

[0118] The total blood volume collected over the 16-28 day period of the study (including the variable screening time) was 279 mL.

[0119] Urine sample (cortisol, creatinine, potassium, sodium, volume): 24-hour urine collection begins around 08:00 on the study day.

[0120] Correlational studies for research / pharmacokinetic studies Plasma samples will be collected to measure the plasma concentrations of the research drug specified in the SOA (Table 1). Samples will be collected for PK evaluation on both days 1 and 10, before administration and at 0.25, 0.5, 1.0, 1.5, 2, 8, and 18 hours after administration. The PK sampling time for the first 120 minutes must be within ±5 minutes of the specified time, after which a ±30 minute window is permitted. Single PK samples will be collected on days 11 and 12 (approximately 24 and 48 hours after the final dose on day 10, respectively) and on day 14.

[0121] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous modifications, changes, and substitutions will be conceivable to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the present invention. The following claims define the scope of the present invention, and it is intended that methods and structures within the scope of these claims and their equivalents are thereby covered.

Claims

1. A method for treating adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in humans, comprising orally administering about 80 mg to about 160 mg of a compound having the structure of compound 1, or a pharmaceutically acceptable salt thereof, once daily. 【Chemistry 1】

2. The method according to claim 1, wherein the human having ACTH-dependent Cushing's syndrome includes a pituitary adenoma.

3. The method according to claim 1, wherein the human having ACTH-dependent Cushing's syndrome includes an ectopic ACTH-secreting tumor.

4. The method according to claim 3, wherein the ectopic ACTH-secreting tumor is located in the lung, pancreas, thyroid gland, thymus, intestine, adrenal gland, paraganglion, or a combination thereof.

5. The method according to any one of claims 1 to 4, wherein treatment of ACTH-dependent Cushing's syndrome comprises lowering serum cortisol levels, lowering urinary cortisol levels, or both.

6. The method according to claim 5, wherein treating ACTH-dependent Cushing's syndrome comprises reducing the cortisol level in the person by at least 10% from baseline.

7. The method according to any one of claims 1 to 6, wherein treating ACTH-dependent Cushing's syndrome comprises reducing levels of serum cortisol, androstenedione, or a combination thereof.

8. The method according to claim 7, wherein treating ACTH-dependent Cushing's syndrome comprises reducing serum cortisol, androstenedione, or a combination thereof, by at least 10% from baseline.

9. The method according to any one of claims 1 to 6, wherein treating ACTH-dependent Cushing's syndrome comprises reducing the levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof.

10. The method according to claim 9, wherein treating ACTH-dependent Cushing's syndrome involves reducing the levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or a combination thereof by at least 10% from baseline.

11. The method according to any one of claims 1 to 10, wherein treating ACTH-dependent Cushing's syndrome includes delaying or eliminating the need for removal of one or both adrenal glands.

12. The method according to any one of claims 1 to 11, wherein approximately 80 mg, approximately 120 mg, or approximately 160 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered.

13. The method according to any one of claims 1 to 11, wherein approximately 80 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered.

14. The method according to any one of claims 1 to 11, wherein approximately 120 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered.

15. The method according to any one of claims 1 to 11, wherein approximately 160 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered.

16. The method according to any one of claims 1 to 15, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once daily in the evening.

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