US20170020877A1 - Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia - Google Patents

Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia Download PDF

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US20170020877A1
US20170020877A1 US15/113,362 US201515113362A US2017020877A1 US 20170020877 A1 US20170020877 A1 US 20170020877A1 US 201515113362 A US201515113362 A US 201515113362A US 2017020877 A1 US2017020877 A1 US 2017020877A1
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Dimitri E. Grigoriadis
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Neurocrine Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones

Definitions

  • compositions and methods for treating congenital adrenal hyperplasia are described herein.
  • CAH Congenital adrenal hyperplasia
  • Non-classic CAH patients are either homozygous or compound heterozygotes, often with a classical CAH allele. These patients have sufficient enzyme activity (>20-50% of normal) such that they do not have salt-wasting or cortisol deficiency and have normal genitalia at birth, and many remain asymptomatic throughout life (Trapp et al., Steroids 77(4):342-46 (2012)). In the less frequent form of the disease, which accounts for 5% of cases, mutation of the 11 ⁇ -hydroxylase gene CYP11B1 results in CAH (11 ⁇ -OH CAH).
  • Corticotropin-releasing factor activates the CRF 1 receptor, a class B G protein-coupled receptor (GPCR).
  • CRF 1 antagonists have the potential to directly inhibit ACTH release in patients with CAH, thereby allowing normalization of androgen production while using lower, more physiologic doses of hydrocortisone, and reducing treatment-associated side effects.
  • the CRF 1 antagonist has a dissociation half-life (t 1/2 ) in excess of 30 minutes, and in another embodiment in excess of 40 minutes, and in another embodiment in excess of 50 minutes.
  • Embodiment 1 A method for treating Congenital Adrenal Hyperplasia (CAH) by administering to a subject in need thereof a CRF 1 receptor antagonist having a dissociation half-life in excess of 30 minutes.
  • CAH Congenital Adrenal Hyperplasia
  • Embodiment 2 The method of Embodiment 1 wherein the CRF 1 receptor antagonist has a dissociation half-life in excess of 40 minutes.
  • Embodiment 3 The method of Embodiment 1 wherein the CRF 1 receptor antagonist has a dissociation half-life in excess of 50 minutes.
  • Embodiment 4 The method of any one of Embodiments 1-3 wherein the CRF 1 receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine).
  • the CRF 1 receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine).
  • Embodiment 5 The method of any one of Embodiments 1-3 wherein the CRF 1 receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904.
  • the CRF 1 receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904.
  • Embodiment 6 The method of any one of Embodiments 1-5 wherein the CRF 1 receptor antagonist is administered at bedtime.
  • Embodiment 7 The method of any one of Embodiments 1-6 wherein the CRF 1 receptor antagonist is administered at or before the expected circadian release of ACTH.
  • Embodiment 8 The method of Embodiment 7 wherein the CRF 1 receptor antagonist is administered 3-4 hours before the expected circadian release of ACTH.
  • Embodiment 9 A method for reducing 17-OHP and ACTH levels in a subject who has Congenital Adrenal Hyperplasia (CAH), said method comprising administering to the subject a CRF 1 receptor antagonist at bedtime.
  • CAH Congenital Adrenal Hyperplasia
  • Embodiment 10 The method of Embodiment 9, wherein the CRF 1 receptor antagonist is administered at or before the expected circadian release of ACTH.
  • Embodiment 11 The method of Embodiment 9 or Embodiment 10, wherein the CRF 1 receptor antagonist is administered 3-4 hours before the expected circadian release of ACTH.
  • Embodiment 12 The method of any one of Embodiments 9-11, wherein the CRF 1 receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine).
  • the CRF 1 receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine).
  • Embodiment 13 The method of any one of Embodiments 9-11, wherein the CRF 1 receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904.
  • the CRF 1 receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904.
  • Embodiment 14 A CRF 1 receptor antagonist for use in treating Congenital Adrenal Hyperplasia (CAH), wherein the CRF 1 receptor antagonist has a dissociation half-life in excess of 30 minutes.
  • CAH Congenital Adrenal Hyperplasia
  • Embodiment 15 The CRF 1 receptor antagonist of 14, wherein the CRF 1 receptor antagonist has a dissociation half-life in excess of 40 minutes.
  • Embodiment 16 The CRF 1 receptor antagonist of Embodiment 14, wherein the CRF 1 receptor antagonist has a dissociation half-life in excess of 50 minutes.
  • Embodiment 17 The CRF 1 receptor antagonist of any one of Embodiments 14-16, wherein the CRF 1 receptor antagonist is Compound I (NBI-77860; 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine).
  • Embodiment 18 The CRF 1 receptor antagonist of any one of Embodiments 14-16, wherein the CRF 1 receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904.
  • the CRF 1 receptor antagonist is NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904.
  • Embodiment 19 The CRF 1 receptor antagonist of any one of Embodiments 14-18, wherein the CRF 1 receptor antagonist is suitable for administration at bedtime.
  • Embodiment 20 The CRF 1 receptor antagonist of any one of Embodiments 14-19, wherein the CRF 1 receptor antagonist is suitable for administration at or before the expected circadian release of ACTH.
  • Embodiment 21 The CRF 1 receptor antagonist of any one of Embodiments 14-20, wherein the CRF 1 receptor antagonist is suitable for administration 3-4 hours before the expected circadian release of ACTH.
  • the methods and uses described above and herein further comprise reducing the amount of a glucocorticoid or mineralocorticoid by at least 10%, 15%, 20%, 30%, 40%, 50%, 60% from the recommended daily dose of GC (such as hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone) administered to a full grown subject (e.g., a human subject) who has CAH.
  • GC such as hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone
  • the methods and uses described above and herein further comprise reducing the amount of a glucocorticoid or mineralocorticoid by at least 10%, 15%, 20%, 30%, 40%, 50%, 60% from the recommended daily dose of GC (e.g., hydrocortisone) or mineralocorticoid (e.g., fludrocortisone) administered to a growing subject (e.g., a human subject) who has CAH.
  • GC e.g., hydrocortisone
  • mineralocorticoid e.g., fludrocortisone
  • a non-human animal may refer to one or more non-human animals, or a plurality of such animals
  • reference to “a cell” or “the cell” includes reference to one or more cells and equivalents thereof (e.g., plurality of cells) known to those skilled in the art, and so forth.
  • FIG. 1 shows a schematic of steroid synthetic pathways in the adrenal gland.
  • the most common form of CAH is caused by 21-hydroxylase (also called 21- ⁇ hydroxylase) deficiency resulting in a decrease of cortisol and increase in androgens such as testosterone and estrogen.
  • 21-hydroxylase also called 21- ⁇ hydroxylase
  • a more rare type of classical CAH is 11 ⁇ -hydroxylase deficiency.
  • FIG. 2 presents a graph illustrating the effect of Compound I (NBI-77860) on ACTH concentration in adrenalectomized rats. Rats received 30 mg/kg of Compound I (NBI-77860) orally. Data are presented as mean plasma concentration of ACTH ( ⁇ SEM).
  • FIGS. 3A-C present graphs illustrating the effect of CRF 1 receptor antagonists, differentiated by their dissociation half-life, on ACTH concentration in adrenalectomized rats.
  • FIG. 4 presents the study design schematic for the clinical trial described in Example 6 that was designed to assess the safety, tolerability and plasma exposure of NBI-77860, as well as the effect of this compound on endogenous levels of HPA (hypothalamic-pituitary-adrenal) axis hormones.
  • HPA hypothalamic-pituitary-adrenal
  • FIG. 5 presents the data for mean 17-OHP (upper panel) and ACTH levels (lower panel) throughout the 24-hour postdose period for the clinical trial described in Example 6.
  • FIG. 6 presents the response of a specific individual subject for 17-OHP (upper panel) and ACTH levels (lower panel) following administration of 300 mg and 600 mg NBI-77860 and placebo over time.
  • CRF 1 receptor antagonists have been found to directly inhibit ACTH release in patients with CAH and thereby allow normalization of androgen production.
  • Administration of a CRF 1 receptor antagonist permits use of lower, more physiologic doses of hydrocortisone in subjects with CAH and thus reduces treatment-associated side effects.
  • Newborn screening for CAH is performed by immunoassay to measure 17-OHP levels in heel-stick capillary blood specimens obtained within the first 72 hours of life.
  • the blood sample is analyzed for 17-OHP by commercially available dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA; PerkinElmer, Waltham Massachusetts) (White et al., J. Pediatr. 163:10-12 (2013)).
  • DELFIA dissociation-enhanced lanthanide fluoroimmunoassay
  • Second-tier screening tests utilizing biochemical and molecular genetic testing methods are employed by nine states in the United States and strongly recommended by an additional 5 states.
  • the biochemical method includes immunoassay with organic solvent extraction or liquid chromatography followed by tandem mass spectrometry to measure steroid ratios of 17-OHP, androstenedione, and 21-deoxycortisol to cortisol (see, e.g., Lucasr et al., Int. J. Pediatr. Endocrinol. 2010:494173, 2010).
  • the genetic screen looks for CYP21A2 mutations that are associated with CAH. While not widely employed in the U.S., the addition of a second screening could potentially improve the sensitivity of the overall screening process, where sensitivity of the first screen alone is approximately 72%.
  • CAH Treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood.
  • Glucocorticoids are the current standard treatment in CAH and are used both to correct the endogenous cortisol deficiency and for reducing the elevated ACTH levels from the pituitary, which drives increased androgen production.
  • Addison's disease adrenal insufficiency
  • cortisol replacement the treatment of CAH must also reduce ACTH production, to control the subsequent androgen excess as well.
  • glucocorticoid treatment includes cortisol replacement and suppression of ACTH to prevent virilization and menstrual disturbances in women and to inhibit testicular adrenal rest tumors in men.
  • Mineralocorticoid replacement is needed to achieve normal plasma renin activity for maintenance of regular blood pressure, electrolyte balance, and volume status in those patients with the salt-wasting form of CAH.
  • glucocorticoid treatment must support normal physiology and also ensure that sufficient cortisol is available during events that may elicit a strong stress response (e.g., intercurrent illness, exercise, hypotension). Careful monitoring is also necessary to avoid the development of iatrogenic Cushing's syndrome due to glucocorticoid overtreatment in an effort to adequately suppress androgen production, or Addisonian syndrome due to under-treatment. Overtreatment with mineralocorticoids may cause hypertension while under-treatment may lead to low blood pressure, salt loss, fatigue and increased requirements for glucocorticoids. Typical laboratory tests for monitoring treatment efficacy include measurement of plasma concentrations of 17-OHP, androstenedione, testosterone, renin activity, and electrolytes.
  • Treatment of CAH includes efforts to normalize the cortisol deficiency with glucocorticoids (usually hydrocortisone in children but often more potent agents with narrow therapeutic indices, such as dexamethasone, in adults) and, if necessary for salt-wasting, mineralocorticoids (usually fludrocortisone).
  • glucocorticoids usually hydrocortisone in children but often more potent agents with narrow therapeutic indices, such as dexamethasone, in adults
  • mineralocorticoids usually fludrocortisone
  • Corticotropin-releasing factor was isolated from ovine hypothalami and identified as a 41-amino acid peptide.
  • CRF has been found to produce profound alterations in endocrine, nervous, and immune system function.
  • CRF is believed to be the major physiological regulator of the basal and stress-induced release of adrenocorticotropic hormone (“ACTH”), ⁇ -endorphin, and other pro-opiomelanocortin (“POMC”)-derived peptides from the anterior pituitary (see, e.g., Vale et al., Science 213:1394-1397, 1981).
  • Secretion of CRF causes release of ACTH from corticotrophs in the anterior pituitary via binding to the CRF 1 receptor, a member of the class B family of G-protein coupled receptors.
  • the pituitary hormone ACTH under the control of hypothalamic corticotropin-releasing factor (CRF), stimulates uptake of cholesterol and drives the synthesis of pregnenolone initiating steroidogenesis in the adrenal gland (see FIG. 1 ).
  • the adrenal cortex is comprised of three zones, which produce distinct classes of hormones many of which are driven by ACTH mobilizing cholesterol through this pathway. Deficiencies in these enzymes as a result of mutation or deletion cause the substrate concentrations to increase.
  • CAH resulting from mutations or deletions in the 21-hydroxylase gene (CYP21A2)
  • CYP21A2 21-hydroxylase gene
  • potent androgens are produced by the adrenal because of the accumulation of the steroid precursors, progesterone and 17-hydroxyprogesterone (17-OHP).
  • Plasma levels of 17-OHP can reach 10-1000 times the normal concentration in these cases. These increases result in the overproduction of androgens, specifically androstenedione, testosterone, and dihydroxytestosterone causing virilization in females.
  • 21-hydroxylase deficiency in CAH causes insufficient biosynthesis of glucocorticoids and mineralocorticoids, specifically cortisol and aldosterone.
  • Cortisol is a critical negative feedback regulator of hypothalamic CRF secretion and pituitary ACTH release. The lack of glucocorticoid synthesis and release eliminates the restraint on the hypothalamus and pituitary, which causes ACTH levels to increase. The excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis resulting in adrenal hyperplasia.
  • a CRF 1 receptor antagonist useful for the treatment of CAH is NBI-77860, 2,5-dimethyl-3-[2-methyl-4-(methyloxy)phenyl]-N-[(1S)-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]pyrazolo[1,5-a]pyrimidin-7-amine (also referred to as “Compound I” herein), and which has the following structure.
  • the CRF 1 receptor antagonist useful for the treatment of CAH is a small molecule antagonist as described in U.S. Pat. No. 6,586,456, U.S. Pat. No. 6,806,282, U.S. Pat. No. 6,531,475, U.S. Pat. No. 6,664,261, U.S. Pat. No.
  • the CRF 1 receptor antagonist is NBI-30775, CP-316,311, pexacerfont, emicerfont, SSR-125543 [4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine], SSR-126374, ONO-2333, NBI-34041, JNJ-19567470, GSK586529, PF-00572778, CP-376395, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), and DMP904.
  • the CRF 1 receptor antagonist has a dissociation half-life (t 1/2 ) in excess of 30 minutes, and in another embodiment in excess of 40 minutes, and in another embodiment in excess of 50 minutes.
  • the dissociation half-life of a particular CRF 1 receptor antagonist is determined by the technique disclosed in Example 3.
  • Representative CRF 1 receptor antagonists of these embodiments include Compound I, NBI-30775, NBI-34041, SSR-125543A, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), and DMP904.
  • H hydrogen
  • D deuterium
  • Incorporation of deuterium in place of hydrogen is known to produce significant effects on the physiological and pharmacological activities of the substituted compound.
  • deuterium replacement of hydrogen means that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium. Accordingly, in one embodiment representative compounds include the following.
  • NBI-77860 2,5-dimethyl-3-[2- methyl-4- (methyloxy)phenyl]-N- [(1S)-1-(3-methyl-1,2,4- oxadiazol-5- yl)propyl]pyrazolo[1,5- a]pyrimidin-7-amine
  • NBI-77860 2,5-dimethyl-3-[2- methyl-4-(d 3 - methyloxy)phenyl]-N- [(1S)-1-(3-methyl-1,2,4- oxadiazol-5- yl)propyl]pyrazolo[1,5- a]pyrimidin-7-amine
  • Deuterated NBI-77860 2,5-dimethyl-3-[2- methyl-4- (methyloxy)phenyl]-N- [(1S)-1-(3-d 3 -methyl- 1,2,4-oxadiazol-5- yl)propyl]pyrazolo[1,5- a]pyrimidin-7-amine
  • any of the aforementioned compounds may incorporate stable or radioactive isotopes.
  • isotopically-labeled compounds identical to those described herein, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into these compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to deuterium as discussed above (2H), as well as 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3H and 14C are incorporated, are also useful in drug or substrate tissue distribution assays.
  • Tritiated hydrogen (3H) and carbon-14 (14C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Substitution with heavier isotopes such as deuterium (2H) can provide certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dose requirements and, therefore, may be preferred in some circumstances.
  • Isotopically-labeled compounds can generally be prepared by performing procedures routinely practiced in the art.
  • Adrenalectomy eliminates circulating corticosterone (the primary glucocorticoid) in rats and removes the negative feedback control of the HPA axis at both the hypothalamic and pituitary (corticotroph cells) levels and thus chronically elevates plasma ACTH (see, e.g., Mims et al., J. Natl. Med. Assoc. 69:145-47 (1977)).
  • Intravenous injection of peptide CRF 1 receptor antagonists have been demonstrated to reduce the high plasma ACTH levels in adrenalectomized (ADX) rats (see, e.g., Rivier et al., J. Med. Chem. 12:42:3175-82 (1999)).
  • NBI-77860 small molecule NBI-77860
  • Compound I has potent capability for lowering ACTH.
  • the maximum reduction in ACTH correlated with peak plasma concentrations of NBI-77860; however, the duration of the ACTH-lowering effect exceeded drug plasma exposure.
  • a predictable relationship therefore exists between integrated plasma exposure of NBI-77860 and in vivo efficacy following oral administration.
  • CRF antagonists described herein may be capable of inhibiting the specific binding of CRF to its receptor and consequently antagonizing activities associated with CRF.
  • a compound may be assessed for activity as a CRF antagonist by one or more generally accepted assays including the assay described in the Examples.
  • CRF antagonists useful for the methods described herein include compounds that demonstrate affinity for CRF receptor.
  • CRF receptor antagonists would potentially block the release of ACTH from pituitary corticotrophs, thereby decreasing the production of androgens, and allow a more refined treatment paradigm for replacement of cortisol.
  • Animal and human studies have shown the pharmacologic effect of Compound I (NBI-77860) on ACTH release. Standard biomarker assessments used by endocrinologists when monitoring treatment efficacy may be used for monitoring the effects of this CRF 1 receptor antagonist. Plasma levels of 17-OHP, androstenedione, testosterone, cortisol and ACTH, as well as urinary metabolites of these steroids, are easily measured in both children and adults giving rapid and meaningful data regarding treatment impact.
  • the present disclosure further provides for pharmaceutical compositions comprising any one of the CRF antagonist compounds described herein and a pharmaceutically acceptable excipient for use in the methods for treating CAH.
  • a pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the active ingredient; an excipient also may be called a carrier.
  • the CRF antagonist compounds may be formulated in a pharmaceutical composition for use in treatment or preventive (or prophylactic) treatment (e.g., reducing exacerbation of CAH disease, or occurrence or recurrence of one or more symptoms of the disease).
  • the methods and excipients described herein are exemplary and are in no way limiting.
  • compositions are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).
  • pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.
  • Therapeutic and/or prophylactic benefit includes, for example, an improved clinical outcome, both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow or retard (lessen) an undesired physiological change or disorder, or to prevent or slow or retard (lessen) the expansion or severity of such disorder.
  • beneficial or desired clinical results from treating a subject include, but are not limited to, abatement, lessening, or alleviation of symptoms that result from or are associated the disease, condition, or disorder to be treated; decreased occurrence of symptoms; improved quality of life; longer disease-free status (i.e., decreasing the likelihood or the propensity that a subject will present symptoms on the basis of which a diagnosis of a disease is made); diminishment of extent of disease; stabilized (i.e., not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission (whether partial or total), whether detectable or undetectable; and/or overall survival.
  • Treatment can also mean prolonging survival when compared to expected survival if a subject were not receiving treatment.
  • Subjects in need of treatment include those who already have the condition or disorder as well as subjects prone to have or at risk of developing the disease, condition, or disorder, and those in which the disease, condition, or disorder is to be prevented (i.e., decreasing the likelihood of occurrence of the disease, disorder, or condition).
  • a subject may be a human or non-human mammal (e.g., rat, mouse, dog, cat, livestock, zoo animal).
  • Optimal doses may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject.
  • the amount of a compound described herein, that is present in a dose ranges from about 0.1 mg to about 30 mg per kg weight of the subject.
  • a single dose is about 50-1000 mg.
  • the use of the minimum dose that is sufficient to provide effective therapy is usually preferred.
  • Subjects may generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • the level of a compound that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
  • a biological fluid for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound may be used to measure the level of compound during the course of a therapeutic regimen.
  • the dose of a composition comprising at least one of the compounds described herein for treating CAH or a related disease or disorder may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the compound may be determined according to parameters understood by a person skilled in the medical art.
  • compositions described herein that comprise at least one of the CRF 1 antagonist compounds described herein may be administered to a subject in need by any one of several routes that effectively deliver an effective amount of the compound.
  • routes include, for example, oral, parenteral, enteral, rectal, intranasal, buccal, sublingual, intramuscular, and transdermal. Compositions administered by these routes of administration and others are described in greater detail herein.
  • bedtime administration refers to dosing intended to deliver clinically relevant concentrations of the CRF 1 antagonist at or before (such as 2-5 hours before) the expected circadian release of ACTH. Since this ACTH release is typically at 1-2 A.M., and since most orally administered drugs have a Tmax of several hours, dosing at 10 P.M., for example, which is 3-4 hours in advance of the expected circadian release of ACTH is desirable.
  • This same pre-pulse bedtime dosing may be adapted for shift workers (e.g., those who work at night and sleep during the day), in which case administration will not necessarily occur at nighttime.
  • a CRF 1 receptor antagonist described herein for example, NBI-77860 or any one of NBI-30775, NBI-34041, SSR-126374, SSR-125543, antalarmin (N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine), or DMP904) is administered between about 2-5 hours prior to (i.e., before, in advance of) the expected circadian release of ACTH.
  • the CRF 1 receptor antagonist is administered to the subject between about 2-4 hours or 3-5 hours prior to the expected circadian release of ACTH. In a more specific embodiment, CRF 1 receptor antagonist is administered to the subject between about 3-4 hours prior to the expected circadian release of ACTH.
  • the antagonist is administered at or before the expected circadian release of ACTH.
  • the CRF 1 receptor antagonist as administered between about 2-4 hours or between about 3-5 hours prior to the expected circadian release of ACTH.
  • CRF 1 receptor antagonist is administered to the subject between about 3-4 hours prior to the expected circadian release of ACTH.
  • the methods described herein that comprise administering a CRF 1 receptor antagonist to a female subject in need thereof in the manner described herein that causes a decrease in level of ACTH and 17-OHP in the subject may result in decreased release of androgens such as testosterone and androstenedione.
  • the dose of glucocorticoids may concomitantly be decreased by a clinically significant amount, which in turn results in decreased side effects.
  • glucocorticoids glucocorticoids
  • MC mineralocorticoids
  • methods for treating CAH by administering a CRF 1 receptor antagonist may further comprise administering a GC at a dose lower than the currently recommended dose of a GC for treating a subject who has CAH.
  • the dose of a GC such as the dose of hydrocortisone (HC), prednisone, prednisolone, dexamethasone, or fludrocortisone recommended for maintenance therapy in a fully grown subject may be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more from the recommended doses of 15-25 mg/day HC; 5-7.5 mg/day prednisone, 4-6 mg/day prednisolone; 0.25-0.5 mg/day dexamethasone, or 0.05-0.2 mg/day of fludrocortisone.
  • HC hydrocortisone
  • prednisone prednisone
  • prednisolone prednisolone
  • dexamethasone dexamethasone
  • the recommended dose of GCs such as HC may be decreased from the total recommended dose of 10-15 mg/m 2 per day and/or the total dose of fludrocortisone of 0.05-0.2 mg/day may each be decreased by about 10%, 15%, 20%, 30%, 40%, 50%, 60% or more in a subject who receives a CRF 1 receptor antagonist as described herein.
  • the methods described herein comprising administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of ACTH levels relative to placebo.
  • administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of ACTH levels relative to placebo, wherein that reduction is at least 25%.
  • administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of ACTH levels relative to placebo, wherein that reduction is at least 50%. Seefeldr et al., supra, for guidelines regarding administering glucocorticoids and mineralocorticoids.
  • the methods described herein comprising administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of 17-OHP levels relative to placebo.
  • administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of 17-OHP levels relative to placebo wherein that reduction is at least 25%.
  • administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of 17-OHP levels relative to placebo wherein that reduction is at least 50%.
  • the methods described herein comprising administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of both ACTH and 17-OHP levels relative to placebo.
  • administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of both ACTH and 17-OHP levels relative to placebo wherein the reduction is at least 25%.
  • administering to a subject in need thereof an effective amount of a CRF 1 antagonist results in a clinically significant reduction of both ACTH and 17-OHP levels relative to placebo wherein the reduction is at least 50%.
  • compositions may be in the form of a solution. Alternatively, they may be in the form of a solid, such as powder, tablets, or the like.
  • a composition comprising any one of the compounds described herein may be formulated for sustained or slow release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of active compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition to be treated or prevented.
  • At least one of the compounds described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders; with disintegrators; with lubricants; and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the compounds may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a compound included in the compositions may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • Oral formulations may be provided as gelatin capsules, which may contain the active compound along with powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar carriers and diluents may be used to make compressed tablets.
  • CRF antagonists as used in the methods described herein may be evaluated for binding activity to the CRF receptor by a standard radioligand binding assay as generally described by Grigoriadis et al. (see, e.g., Mol. Pharmacol vol 50, pp 679-686, 1996) and Hoare et al. (see, e.g., Mol. Pharmacol 63: 751-765, 2003.)
  • the assay may be used to evaluate the binding activity of the compounds described herein with any CRF receptor subtype.
  • the binding assay involves the displacement of a radiolabeled CRF ligand from the CRF receptor. More specifically, the binding assay is performed in 96-well assay plates using 1-10 ⁇ g cell membranes from cells stably transfected with human CRF receptors.
  • Each well receives about 0.05 mL assay buffer (e.g., Dulbecco's phosphate buffered saline, 10 mM magnesium chloride, 2 mM EGTA) containing compound of interest or a reference ligand (for example, sauvagine, urocortin I, or CRF), 0.05 mL of [ 125 I] tyrosine—sauvagine (final concentration ⁇ 150 pM or approximately the K D as determined by Scatchard analysis) and 0.1 mL of a cell membrane suspension containing the CRF receptor.
  • the mixture is incubated for 2 hours at 22° C. followed by separation of the bound and free radioligand by rapid filtration over glass fiber filters.
  • radioactivity is counted using a scintillation counter. All radioligand binding data may be analyzed using the non-linear least-squares curve-fitting programs Prism (GraphPad Software Inc) or XLfit (ID Business Solutions Ltd).
  • K i k ⁇ 1 /k i
  • the dissociation half-life (t 1/2 ) of a CRF 1 receptor antagonist as used in the methods described herein is evaluated by the technique described in Fleck et al.
  • the dissociation rate constant for labeled and unlabeled ligands is denoted as k ⁇ 1
  • the half-life of drug dissociation from the receptor (t 1/2 ) is calculated from the dissociation rate constant (k ⁇ 1 ) by the following equation:
  • CRF 1 receptor antagonists that have a dissociation half-life (t 1/2 ) in excess of 30 minutes include (but are not limited to) antalarim, NBI-34041, DMP904, NBI-30775, SSR125543A, and NBI-77860 (Compound I). These same compounds are also representative of CRF 1 receptor antagonists having a dissociation half-life (t 1/2 ) in excess of 40 minutes, and a dissociation half-life (t 1/2 ) in excess of 50 minutes.
  • Compound I (NBI-77860) (see, e.g., Tellew et al., Bioorg. Med. Chem. Lett. 2010, 20:7259; WO2006044958) is a potent CRF 1 antagonist possessing a binding pKi of 8.2, a kinetic Ki of 49 nM (Table 1 above), and a Dissociation t 1/2 of 58 minutes (Table 2 above).
  • NBI-77860 Compound I
  • Metyrapone blocks cortisol synthesis in the adrenal, thereby mimicking the cortisol deficiency of CAH, and is associated with an acute reflex rise ACTH levels.
  • the primary analysis was performed by determining the ACTH values between 30 min and 4 h post dose (AUC (30 min to 4 h)). In this analysis, when compared to placebo, the following observations were made. A significant reduction of ACTH AUC (30 min to 4 h) was observed with the alprazolam and the NBI-77860, 400 mg treatments. A non-significant reduction in ACTH AUC (30 min to 4 h) was seen with the NBI-77860, 50 mg treatment. An increase in AUC (30 min to 4 h) was seen with the NBI-77860, 10 mg treatment.
  • NBI-77860 (Compound I) was evaluated in the clinical study entitled “A Phase 1, Single-Blind, Placebo-Controlled, Fixed-Sequence, Single-Dose Study to Evaluate the Safety and Tolerability of NBI-77860 in Adult Females with Congenital Adrenal Hyperplasia” (IND 117,388).
  • the study was a single-blind, placebo-controlled, single center, fixed-sequence, single-dose clinical trial in adult female classical CAH patients. It was designed to assess the safety, tolerability, and plasma exposure of NBI-77860, as well as the effect of this compound on endogenous levels of HPA axis hormones.
  • a total of 8 female subjects, ages 19 to 58, with a medical diagnosis of classical 21-hydroxylase deficiency CAH were administered single bedtime doses (hs) of NBI-77860 300 mg, 600 mg, and placebo during three separate treatment periods (see study design schematic in FIG. 4 ).
  • the subjects' usual morning dose of concurrent steroidal treatment was delayed until after the 16-hour postdose blood samples were collected (i.e., until approximately 1400 h).
  • the PD endpoints for this study included the HPA axis biomarkers of interest in this patient population; namely, 17-hydroxyprogesterone (17-OHP; as the primary PD endpoint), adrenocorticotropic hormone (ACTH), androstenedione, testosterone, and serum cortisol levels.
  • the initial analysis of PD variables was an examination of the grouped subject data for each biomarker, expressed as a mean percent change from predose levels for the two active dosing conditions relative to the placebo condition.
  • the data for mean 17-OHP and ACTH levels throughout the 24-hour postdose period are provided in FIG. 5 .

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