(12) Unlted States Patent
`(10) Patent No.:
`US 7,361,646 B2
`
`Belanofl
`(45) Date of Patent:
`Apr. 22, 2008
`
`USOO7361646B2
`
`(54) METHODS FOR TREATING
`GASTROESOPHAGEAL REFLUX DISEASE
`
`(75)
`
`Inventor:
`
`«(10531311 K- 391311017, Woodside, CA
`US
`
`(73) Assignee: Corcept Therapeutics, Inc., Menlo
`Park, CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 556 days.
`
`(21) Appl. No.: 10/702,950
`
`(22) Flled'
`(65)
`
`NOV' 5’ 2003
`Prior Publication Data
`US 2004/0167110 A1
`Aug. 26, 2004
`
`Related US. Application Data
`
`(60) Provisional application No. 60/424 199 filed on Nov.
`5 2002.
`’
`Int. Cl.
`A61K 31/56
`A61K 31/573
`
`(2006.01)
`(2006.01)
`
`(51)
`
`....................................... 514/179; 514/178
`(52) US. Cl.
`(58) Field of Classification Search ................ 514/179,
`514/178
`See application file for complete search history.
`References Cited
`
`(56)
`
`US. PATENT DOCUMENTS
`4,753,932 A
`6/1988 Teutsch et al.
`4,912,097 A
`3/ 1990 Teutsch et a1.
`5,697,112 A * 12/1997 Colavito et al.
`6,011,025 A
`1/2000 Gebhard
`6,380,223 B1
`4/2002 Dow et al.
`
`............... 5/633
`
`* cited by examiner
`
`Primary Examinerilennifer Kim
`(74) Attorney, Agent, or FirmiTownsend and Townsend
`and Crew LLP
`
`(57)
`
`ABSTRACT
`
`This invention relates to the discovery that agents capable of
`inhibiting the biological action of the glucocorticoid recep-
`tor can be used in methods for treating gastroesophageal
`reflux disease in a subject.
`
`14 Claims, N0 Drawings
`
`

`

`US 7,361,646 B2
`
`1
`METHODS FOR TREATING
`GASTROESOPHAGEAL REFLUX DISEASE
`
`CROSS REFERENCES TO RELATED
`APPLICATIONS
`
`This application claims priority to US. 60/424,199, filed
`NOV. 5, 2002, which is incorporated herein by reference in
`its entirety.
`
`FIELD OF THE INVENTION
`
`This invention relates to the discovery that agents capable
`of inhibiting the biological action of the glucocorticoid
`receptor can be used in methods for reducing, eliminating, or
`preventing gastroesophageal reflux disease in a subject.
`
`BACKGROUND OF THE INVENTION
`
`Gastroesophageal reflux disease (GERD) is a chronic,
`relapsing condition with associated morbidity and an
`adverse impact on quality of life. The disease is common,
`with an estimated lifetime prevalence of 25 to 35 percent in
`the US. population. Psychological well-being question-
`naires indicate that patients with GERD can have a poor
`quality of life. Indeed, the combination of symptoms, dietary
`restrictions, and functional limitations take their toll on an
`individual’s sense of well-being.
`In addition to the poor quality of life experienced by
`GERD sufferers, annual health care costs related to this
`disease are high. Individuals who suffer from GERD are
`prone to complications such as severe esophagitis, recurrent
`esophageal strictures, severe pulmonary symptoms, and
`Barrett’s esophagus, which carries with it an increased risk
`for the development of adenocarcinoma of the esophagus.
`Antacids remain the drugs of choice for quick relief of
`symptoms associated with GERD. These agents act prima-
`rily by rapidly increasing the pH of the gastric refluxate.
`Although antacids are effective in relieving symptoms, they
`cannot be used as sole agents for achieving esophageal
`healing because of the high dosage requirements and con-
`sequent lack of patient compliance.
`Over-the-Counter H2-Receptor Blockers may also be pre-
`scribed for the treatment and prevention of GERD. These
`agents are indicated for the prevention and relief of heart-
`burn, acid indigestion and sour stomach. They do not act as
`rapidly as antacids, but they provide longer relief of symp-
`toms. Unfortunately, standard dosages of these agents do not
`completely inhibit acid secretion, and so do not typically
`promote esophageal healing.
`Clearly, there is a need in the art for a safe and effective
`GERD treatment that will reduce and/or eliminate the causes
`
`and/or symptoms of GERD. The ideal treatment would also
`promote healing of damaged esophageal tissues,
`thereby
`reducing health cost associated with the disease. Fortunately,
`the current invention addresses these and other needs. The
`
`invention is based, at least in part, on the surprising discov-
`ery that glucocorticoid receptor antagonists are effective
`agents for the treatment of GERD.
`Corticosteroids are steroid hormones released by the
`adrenal glands. The most significant human adrenal corti-
`costeroids are cortisol, corticosterone and aldosterone. Cor-
`ticosteroids produce cellular effects following binding to
`receptors located in the cytoplasm of the cell. Two general
`classes of corticosteroid receptors are now recognized, the
`mineralocorticoid receptors (also termed type I, or MR) and
`the glucocorticoid receptors (also termed type II, or GR).
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`Mineralocorticoid receptors (MRs) bind cortisol with
`ten-fold higher aflinity than glucocorticoid receptors (GRs)
`bind glucocorticoids. Thus, the activation of the two classes
`of receptors may differ depending on the corticosteroid
`(cortisol) concentration. Blood levels of the glucocorticoid
`cortisol vary over a wide range during the day. In general,
`normal cortisol concentrations in the blood range from about
`0.5 nM to about 50 nM; however,
`in response to stress,
`cortisol concentration may exceed 100 nM.
`Glucocorticoid blockers are agents that block or reduce
`the effects of glucocorticoids. Such interference with glu-
`cocorticoid action may, for example, be due to interference
`with binding of glucocorticoid agonists to glucocorticoid
`receptors (GR), or to interference with the action of agonist-
`bound GR at
`the cell nucleus, or to interference with
`expression or processing of gene products induced by the
`action of agonist-bound GR at the nucleus. Glucocorticoid
`receptor antagonists (GR antagonists) are compounds which
`inhibit the effect of the native ligand or of glucocorticoid
`agonists on GR. One mode of action of GR antagonists is to
`inhibit the binding of GR ligands to GR. A discussion of
`glucocorticoid antagonists may be found in Agarwal et al.
`“Glucocorticoid antagonists”, FEBS Lett., 217:221-226
`(1987). An example of a GR antagonist is mifepristone,
`(1 18,178)
`1 1 [4(dimethylamino)phenyl]-17hydroxy-17(1
`propynyl)estra-4,9dien-3one, also known as RU-486 or
`RU-38486. See US. Pat. No. 4,368,085. Mifepristone binds
`specifically to GR with an aflinity about 18 times that of the
`aflinity of cortisol for GR. GR antagonists may be steroids,
`such as mifepristone, or non-steroids.
`The present inventors have determined for the first time
`that glucocorticoid receptor antagonists are effective agents
`for the treatment of gastroesophageal reflux disease. Thus,
`the present invention fulfills the need for an effective method
`for the treatment of gastroesophageal reflux disease by
`providing methods of administering glucocorticoid receptor
`antagonists to a subject.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The present invention is based at least in part, upon the
`discovery that administration of a glucocorticoid receptor
`antagonist provides an effective and improved treatment for
`gastroesophageal reflux disease. Thus,
`in one aspect, the
`invention is directed toward methods of treating gastroe-
`sophageal reflux disease in a subject, provided that the
`subject is not otherwise in need of treatment with a gluco-
`corticoid receptor antagonist.
`In one aspect of the invention, the glucocorticoid receptor
`antagonist comprises a steroidal skeleton with at least one
`phenyl-containing moiety in the 11-beta position of the
`steroidal skeleton.
`In one aspect,
`the phenyl-containing
`moiety in the 11-beta position of the steroidal skeleton is a
`dimethylaminophenyl moiety. In another aspect, the gluco-
`corticoid receptor antagonist is mifepristone.
`In one aspect of the present invention, the glucocorticoid
`receptor antagonist is selected from the group consisting of
`1 1 [3-(4-dimethylaminoethoxyphenyl)-170t-propynyl-17B-
`hydroxy-4,9-estradien—3 -one and 17B-hydroxy-17ot-19-(4-
`methylphenyl)androsta-4,9(11)-dien-3-one.
`In
`another
`aspect,
`the glucocorticoid receptor antagonist is selected
`from the group consisting 40t(S)-Benzyl-2(R)-prop-1-ynyl-
`1,2,3 ,4,4(X,9, 1 0, 100t(R) -octahydro -phenanthrene-2,7-diol
`and 40t(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,40t,9,10,100t
`(R)-octahydro-phenanthrene-2,7-diol.
`
`

`

`US 7,361,646 B2
`
`3
`In another one aspect, the glucocorticoid receptor antago-
`nist is (11[3,17B)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-
`(1 -propynyl)estra-4,9-dien-3-one.
`In another aspect of the present invention, the glucocor-
`ticoid receptor antagonist is administered in a daily amount
`of between about 0.5 to about 35 mg per kilogram of body
`weight per day. In another aspect, the glucocorticoid recep-
`tor antagonist is administered in a daily amount of between
`about 5 to about 15 mg per kilogram of body weight per day.
`In one aspect of the present invention, the administration
`is once per day. In yet another aspect, the mode of admin-
`istration is by a transdermal application, by a nebulized
`suspension, or by an aerosol spray. In another aspect, the
`mode of administration is oral.
`
`In another aspect the invention also provides a kit for
`treating gastroesophageal reflux disease in a subject. The kit
`comprises a specific glucocorticoid receptor antagonist and
`an instructional material teaching the indications, dosage
`and schedule of administration of the glucocorticoid recep-
`tor antagonist to a patient suffering from gastroesophageal
`reflux disease.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Definitions
`
`The term “gastroesophageal reflux disease” or “GERD”
`refers to a condition resulting from food or liquid traveling
`from the stomach back up into the esophagus. This partially
`digested material
`is usually acidic and can irritate the
`esophagus, often causing heartburn and other symptoms.
`GERD can be associated with a number of conditions,
`including, but not limited to incompetent esophageal sphinc-
`ters, hiatal hernia, obesity, recurrent or persistent vomiting,
`previous esophageal surgery or esophageal stricture
`The term “prophylactic” refers to an agent that acts to
`prevent disease, such as gastroesophageal reflux disease. In
`one aspect, a glucocorticoid receptor antagonist of the
`invention is administered prophylactically to prevent the
`onset or recurrence of gastroesophageal reflux disease.
`The terms “treating”, “treatment”, “to treat” refer to
`means for reducing or eliminating gastroesophageal reflux
`disease and or the accompanying symptoms in a subject.
`Treatment refers to any indicia of success in reduction,
`elimination, or amelioration of gastroesophageal
`reflux,
`including any objective or subjective parameter such as
`abatement; remission; diminishing of symptoms, or lessen-
`ing of symptoms or making the condition more tolerable to
`the subject; rendering the refluxate harmless,
`improving
`esophageal clearance, protecting the esophageal mucosa; or
`improving a patient’s physical or mental well-being. For
`example, success of treatment by methods of the invention
`could be measured by comparing the severity of gastroe-
`sophageal reflux and the nature of the refluxant in the year
`before treatment with anti-glucocorticoids of the invention
`was initiated, with the year following the initiation of
`treatment. The treatment or amelioration of symptoms can
`be based on objective or subjective parameters; including
`the results of a physical examination, or any other appro-
`priate means known in the art.
`The term “cortisol” refers to a family of compositions also
`referred to as hydrocortisone, and any synthetic or natural
`analogues thereof.
`The term “glucocorticoid receptor” (“GR”) refers to a
`family of intracellular receptors also referred to as the
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`cortisol receptor, which specifically bind to cortisol and/or
`cortisol analogs. The term includes isoforrns of GR, recom-
`binant GR and mutated GR.
`
`The term “mifepristone” refers to a family of composi-
`tions also referred to as RU486, or RU38.486, or 17-[3-
`hydroxy-11-[3-(4-dimethyl-aminophenyl)-17-0t-(1-propy-
`nyl)-estra-4, 9-dien—3 -one),
`or
`11-[3 -
`(4dimethylaminophenyl)-17-[3-hydroxy-17-ot-(1 -propynyl)-
`estra-4,9-dien-3-one), or analogs thereof, which bind to the
`GR, typically with high aflinity, and inhibit the biological
`effects initiated/mediated by the binding of any cortisol or
`cortisol analogue to a GR receptor. Chemical names for
`RU-486 vary; for example, RU486 has also been termed:
`11 [3-[p-(Dimethylamino)phenyl]-17[3-hydroxy-17-(1-pro-
`pynyl) -estra-4,9-dien-3 -one;
`11 [3-(4-dimethyl-aminophe-
`nyl)-17B-hydroxy-17ot-(prop-1-ynyl)-estra-4,9-dien-3 -one;
`17B-hydroxy-1 1 [3-(4-dimethylaminophenyl-1)-170t-(propy-
`nyl-1)-estra-4,9-diene-3-one; 17B-hydroxy-11[3-(4-dimethy-
`laminophenyl-1)-170t-(propynyl-1)-E;
`(118,17B)-11-[4-
`dimethylamino)-phenyl]-17-hydroxy-17-(1-propynyl)estra-
`4,9-dien-3-one; and 11[3-[4-(N,N-dimethylamino)phenyl]-
`170t-(prop-1-ynyl)-D-4,9-estradiene-17[3-ol-3-one.
`The term “specific glucocorticoid receptor antagonist”
`refers to any composition or compound which partially or
`completely inhibits (antagonizes) the binding of a glucocor-
`ticoid receptor (GR) agonist, such as cortisol, or cortisol
`analogs, synthetic or natural, to a GR. By “specific”, we
`intend the drug to preferentially bind to the GR rather than
`the mineralocorticoid receptor (MR) with an affinity at least
`100-fold, and frequently 1000-fold.
`A subject “not otherwise in need of treatment with a
`glucocorticoid receptor antagonist” is an individual or
`patient who is not being treated with antiglucocorticoid
`compounds for any disorder accepted by the medical com-
`munity to be effectively treatable with antiglucocorticoid
`compounds. Conditions known in the art and accepted by the
`medical community to be effectively treatable with gluco-
`corticoid receptor antagonists include: Cushing’s disease,
`drug withdrawal, dementia, stress disorders, anxiety disor-
`ders (U.8. Pat. No. 5,741,787), depression, psychotic major
`depression (U.8. Pat. No. 6,150,349), schizoalfective disor-
`der, diabetes,
`rheumatoid arthritis, autoimmune disease,
`HIV infection, dermatitis, inflammation, fibromyalgia, cen-
`tral nervous system disease, neurodegeneration, neural inju-
`ries, pelvic pain, and various cancers.
`I. Introduction
`
`This invention pertains to the surprising discovery that
`agents that can inhibit glucocorticoid-induced biological
`responses are effective for treating gastroesophageal reflux
`disease.
`In treating gastroesophageal reflux disease,
`the
`methods of the invention can ameliorate, eliminate, reduce
`or prevent the symptoms of gastroesophageal reflux disease.
`In one embodiment, the methods of the invention use agents
`that act as GR antagonists, blocking the interaction of
`cortisol with GR, to treat gastroesophageal reflux disease.
`The methods of the invention are effective in treating
`gastroesophageal reflux disease in an afllicted patient.
`Cortisol acts by binding to an intracellular, glucocorticoid
`receptor (GR).
`In humans, glucocorticoid receptors are
`present in two forms: a ligand-binding GR-alpha of 777
`amino acids; and, a GR-beta isoform that differs in only the
`last fifteen amino acids. The two types of GR have high
`aflinity for their specific ligands, and are considered to
`function through the same signal transduction pathways.
`The biological effects of cortisol, including pathologies or
`dysfunctions caused by hypercortisolemia, can be modu-
`
`

`

`US 7,361,646 B2
`
`5
`lated and controlled at the GR level using receptor antago-
`nists. Several different classes of agents are able to act as GR
`antagonists,
`i.e.,
`to block the physiologic effects of GR-
`agonist binding (the natural agonist
`is cortisol). These
`antagonists include compositions, which, by binding to GR,
`block the ability of an agonist to effectively bind to and/or
`activate the GR. One family of known GR antagonists,
`mifepristone and related compounds, are effective and
`potent anti-glucocorticoid agents in humans (Bertagna, J.
`Clin. Endocrinol. Metab. 59:25, 1984). Mifepristone binds
`to the GR with high aflinity, with a K of dissociation <10—9
`M (Cadepond, Annu. Rev. Med. 48:129, 1997). Thus, in one
`embodiment of the invention, mifepristone and related com-
`pounds are used to treat gastroesophageal reflux disease in
`a subject.
`As the methods of the invention include use of any means
`to inhibit the biological effects of an agonist-bound GR,
`illustrative compounds and compositions which can be used
`to treat gastroesophageal reflux disease in a subject are also
`set forth. Routine procedures that can be used to identify
`further compounds and compositions able to block the
`biological response caused by a GR-agonist interaction for
`use in practicing the methods of the invention are also
`described. As the invention provides for administering these
`compounds and compositions as pharmaceuticals, routine
`means to determine GR antagonist drug regimens and for-
`mulations to practice the methods of the invention are set
`forth below.
`
`11. Diagnosis of Gastroesophageal Reflux Disease in a
`Subject
`Gastroesophageal reflux disease (GERD) is characterized
`by heartburn and regurgitation, which may also include
`dysphagia. The heartburn characteristic of GERD is most
`frequently described as a sub-stemal burning that occurs
`after meals and often worsens when lying down. Other
`symptoms that may be associated with GERD include, but
`are not limited to atypical chest pain, hoarseness, nausea,
`cough, odynophagia and asthma.
`Diagnosis may be made from the presentation of the
`characteristic GERD symptoms alone, but sometimes fur-
`ther tests are needed to confirm the diagnosis of GERD. In
`cases wher further diagnosis is warranted, the further diag-
`nosis is typically made by treating patients with medications
`that suppress the production of acid by the stomach. Acid
`suppressing medications include proton pump inhibitors
`such as Prilosec (omeprazole), Prevacid (lansoprazole), Aci-
`phex (rabeprazole), Protonix (pantoprazole), and Nexium
`(esomeprazole), and histamine blockers such as Zantac
`(ranitidine), Tagamet (cimetidine), and Pepcid (famotidine).
`If the heartburn then is diminished to a large extent, a
`diagnosis of GERD may be confirmed.
`In some cases further diagnostic measures may be carried
`out. For example, if doubts remain about the diagnosis the
`after the above tests are completed, or if complications are
`a concern. The gold standard for diagnosing GERD is
`esophageal acid testing.
`Patients with the symptoms or complications of GERD
`have reflux of more acid, and the acid remains longer in the
`esophagus when compared to healthy individuals. Thus,
`diagnosis of GERD can be confirmed or extended by per-
`forming a 24-hour esophageal pH test. A pH monitor is
`placed in the esophagus above the lower esophageal sphinc-
`ter, and the pH is recorded at regular intervals over a 24-hour
`test period. Combined with a diary of symptoms kept by the
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`patient, this method permits GERD to be diagnosed and
`correlated with the lowering of esophageal pH that occurs
`with reflux.
`
`A method for prolonged measurement (48 hours) of acid
`exposure in the esophagus may also be conducted. The
`method utilizes a small, wireless capsule that is attached to
`the esophagus just above the LES. The capsule measures the
`acid refluxing into the esophagus and transmits this infor-
`mation to a receiver that
`is worn at
`the waist. At
`the
`
`completion of the test, the information from the receiver is
`downloaded into a computer and analyzed. The capsule falls
`off of the esophagus after 3-5 days and is passed in the stool.
`
`111. General Laboratory Procedures
`When practicing the methods of the invention, a number
`of general
`laboratory tests can be used to assist
`in the
`diagnosis, progress and prognosis of the patient with gas-
`troesophageal
`reflux disease,
`including monitoring of
`parameters such as blood cortisol, drug metabolism, brain
`structure and function and the like. These procedures can be
`helpful because all patients metabolize and react to drugs
`uniquely. In addition, such monitoring may be important
`because each GR antagonist has different pharrnacokinetics.
`Different patients and disease conditions may require dif-
`ferent dosage regimens and formulations. Such procedures
`and means to determine dosage regimens and formulations
`are well described in the scientific and patent literature. A
`few illustrative examples are set forth below.
`
`a. Determining Blood Cortisol Levels
`The invention may be practiced upon patients with appar-
`ently normal levels of blood cortisol. However, since the
`treatment for gastroesophageal reflux disease comprises
`administration of a glucocorticoid receptor antagonist,
`monitoring blood cortisol and determining baseline cortisol
`levels are useful laboratory tests to aid in the diagnosis,
`treatment and prognosis of a gastroesophageal reflux disease
`patient. A wide variety of laboratory tests exist that can be
`used to determine whether an individual is normal, hypo- or
`hypercortisolemic. Patients with gastroesophageal
`reflux
`disease typically have normal levels of cortisol that are often
`less than 25 ug/dl in the morning, and frequently about 15
`ug/dl or less in the afternoon, although the values often fall
`at the high end of the normal range, which is generally
`considered to be 5-15 ug/dl in the afternoon.
`lmmunoassays such as radioimmunoassays are com-
`monly used because they are accurate, easy to do and
`relatively cheap. Because levels of circulating cortisol are an
`indicator of adrenocortical function, a variety of stimulation
`and suppression tests, such as ACTH Stimulation, ACTH
`Reserve, or dexamethasone suppression (see, e.g., Green-
`wald, Am. J. Psychiatry 143:442-446, 1986), can also pro-
`vide diagnostic, prognostic or other information to be used
`adjunctively in the methods of the invention.
`One such assay available in kit form is the radioimmu-
`noassay available as “Double Antibody Cortisol Kit” (Diag-
`nostic Products Corporation, Los Angeles, Calif.), (Acta
`Psychiatr. Scand. 70:239-247, 1984). This test is a competi-
`tive radioimmunoassay in which 125l-labeled cortisol com-
`petes with cortisol from an clinical sample for antibody sites.
`In this test, due to the specificity of the antibody and lack of
`any significant protein effect, serum and plasma samples
`require neither preextraction nor predilution. This assay is
`described in further detail in Example 2, below.
`
`b. Determination of Blood/Urine Mifepristone Levels
`Because a patient’s metabolism, clearance rate, toxicity
`levels, etc. differs with variations in underlying primary or
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`US 7,361,646 B2
`
`7
`secondary disease conditions, drug history, age, general
`medical condition and the like,
`it may be necessary to
`measure blood and urine levels of GR antagonist. Means for
`such monitoring are well described in the scientific and
`patent literature. As in one embodiment of the invention
`mifepristone is administered to treat gastroesophageal reflux
`disease, an illustrative example of determining blood and
`urine mifepristone levels is set forth in the Example below.
`
`c. Other Laboratory Procedures
`Laboratory tests monitoring and measuring GR antagonist
`metabolite generation, plasma concentrations and clearance
`rates,
`including urine concentration of antagonist and
`metabolites, may also be useful in practicing the methods of
`the invention. For example, mifepristone has two hydro-
`philic, N—monomethylated and N—dimethylated, metabolites.
`Plasma and urine concentrations of these metabolites (in
`addition to RU486) can be determined using, for example,
`thin layer chromatography, as described in Kawai Pharma-
`col. and Experimental Therapeutics 241:401-406, 1987.
`
`IV. Glucocorticoid Receptor Antagonists to Treat Gastroe-
`sophageal Reflux Disease in a Subject
`The invention provides for methods for treating gastroe-
`sophageal reflux disease in a subject utilizing any compo-
`sition or compound that can block a biological response
`associated with the binding of cortisol or a cortisol analogue
`to a GR. Antagonists of GR activity utilized in the methods
`of the invention are well described in the scientific and
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`patent literature. A few illustrative examples are set forth
`below.
`
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`
`A. Steroidal Anti-Glucocorticoids as GR Antagonists.
`Steroidal glucocorticoid antagonists are administered to
`treat gastroesophageal reflux disease in various embodi-
`ments of the invention. Steroidal antiglucocorticoids can be
`obtained by modification of the basic structure of glucocor-
`ticoid agonists, i.e., varied forms of the steroid backbone.
`The structure of cortisol can be modified in a variety of
`ways. The two most commonly known classes of structural
`modifications of the cortisol steroid backbone to create
`
`glucocorticoid antagonists include modifications of the
`11-beta hydroxy group and modification of the 17-beta side
`chain (see, e.g., Lefebvre, J. Steroid Biochem. 33:557-563,
`1989).
`Examples of steroidal GR antagonists include androgen-
`type steroid compounds as described in U.S. Pat. No.
`5,929,058, and the compounds disclosed in U.S. Pat. Nos.
`4,296,206; 4,386,085; 4,447,424; 4,477,445; 4,519,946;
`4,540,686; 4,547,493; 4,634,695; 4,634,696; 4,753,932;
`4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763;
`4,912,097; 4,921,638; 4,943,566; 4,954,490; 4,978,657;
`5,006,518; 5,043,332; 5,064,822; 5,073,548; 5,089,488;
`5,089,635; 5,093,507; 5,095,010; 5,095,129; 5,132,299;
`5,166,146; 5,166,199; 5,173,405; 5,276,023; 5,380,839;
`5,348,729; 5,426,102; 5,439,913; 5,616,458, 5,696,127, and
`6,303,591. Such steroidal GR antagonists include cortex-
`olone, dexamethasone-oxetanone, 19-nordeoxycorticoster-
`one, 19-norprogesterone, cortisol-21-mesylate; dexametha-
`sone-21 -mesylate,
`1 1 [3-(4 -dimethylaminoethoxyphenyl)-
`170t-propynyl-17B-hydroxy-4,9-estradien-3-one
`(RU009),
`and
`17B-hydroxy-170t-19-(4-methylphenyl)androsta-4,9
`(11)-dien-3-one (RU044).
`Other examples of steroidal antiglucocorticoids are dis-
`closed in Van Kampen et al.
`(2002) Eur. J. Pharrnacol.
`457(2-3):207, WO 03/043640, EP 0 683 172 B1, and EP 0
`763 541 B1, each of which is incorporated herein by
`reference. EP 0 763 541 B1 and Hoyberg et al., Int’l J. of
`Neuro-psychopharmacology, 5:Supp. 1, $148 (2002); dis-
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`close the compound (11B,17[3)-11-(1,3-benzodioxol-5-yl)-
`17-hydroxy-17-(1-propynyl)estra-4,9-dien-3 -one
`(ORG
`34517) which in one embodiment,
`is administered in an
`amount effective to treat gastroesophageal reflux disease in
`a subject.
`1. Removal or Substitution of the 11-beta Hydroxy Group
`Glucocorticoid antagonists with modified steroidal back-
`bones comprising removal or substitution of the 11-beta
`hydroxy group are administered in one embodiment of the
`invention. This class includes natural antiglucocorticoids,
`including cortexolone, progesterone and testosterone deriva-
`tives, and synthetic compositions, such as mifepristone
`(Lefebvre, et al. supra). Preferred embodiments of the inven-
`tion include all 11-beta-aryl steroid backbone derivatives
`because these compounds are devoid of progesterone recep-
`tor (PR) binding activity (Agarwal, FEBS 217:221-226,
`1987). Another preferred embodiment comprises an 11-beta
`phenyl-aminodimethyl steroid backbone derivative,
`i.e.,
`mifepristone, which is both an effective anti-glucocorticoid
`and anti-progesterone agent. These compositions act as
`reversibly-binding
`steroid
`receptor
`antagonists.
`For
`example, when bound to a 11-beta phenyl-aminodimethyl
`steroid, the steroid receptor is maintained in a conformation
`that cannot bind its natural ligand, such as cortisol in the case
`of GR (Cadepond, 1997, supra).
`Synthetic 11-beta phenyl-aminodimethyl steroids include
`mifepristone, also known as RU486, or 17-beta-hydrox-11-
`beta-(4-dimethyl-aminophenyl)17-alpha-(1-propynyl)estra-
`4,9-dien-3-one). Mifepristone has been shown to be a pow-
`erful antagonist of both the progesterone and glucocorticoid
`(GR) receptors. Another 11-beta phenyl-aminodimethyl ste-
`roids shown to have GR antagonist effects includes RU009
`(RU3 9 .009),
`1 1 -beta-(4-dimethyl-aminoethoxyphenyl)-17-
`alpha-(propynyl-l7-beta-hydroxy-4,9-estradien-3-one) (see
`Bocquel, J. Steroid Biochem. Molec. Biol. 45:205-215,
`1993). Another GR antagonist related to RU486 is RU044
`(RU43 .044)
`17-beta-hydrox-17-alpha-19-(4-methyl-phe-
`nyl)-androsta-4,9(11)-dien-3-one) (Bocquel, 1993, supra).
`See also Teutsch, Steroids 38:651-665, 1981; U.S. Pat. Nos.
`4,386,085 and 4,912,097.
`One embodiment includes compositions containing the
`basic glucocorticoid steroid structure which are irreversible
`anti-glucocorticoids. Such compounds include alpha-keto-
`methanesulfonate derivatives of cortisol, including cortisol-
`21-mesylate
`(4-pregnene-11-beta,
`17-alpha,
`21-triol-3,
`20-dione-21-methane-sulfonate and dexamethasone-21-me-
`
`sylate (16-methyl-9alpha-fluoro-1,4-pregnadiene-11 beta,
`17-alpha, 21-triol-3, 20-dione-21-methane-sulfonte). See
`Simons, J. Steroid Biochem. 24:25-32, 1986; Mercier, J.
`Steroid Biochem. 25:11-20, 1986; U.S. Pat. No. 4,296,206.
`2. Modification of the 17-beta Side Chain Group
`Steroidal antiglucocorticoids which can be obtained by
`various structural modifications of the 17-beta side chain are
`also used in the methods of the invention. This class includes
`
`synthetic antiglucocorticoids such as dexamethasone-oxet-
`anone, various 17, 21-acetonide derivatives and 17-beta-
`carboxamide derivatives of dexamethasone (Lefebvre, 1989,
`supra; Rousseau, Nature 279:158-160, 1979).
`3. Other Steroid Backbone Modifications
`
`GR antagonists used in the various embodiments of the
`invention include any steroid backbone modification which
`effects a biological response resulting from a GR-agonist
`interaction. Steroid backbone antagonists can be any natural
`or synthetic variation of cortisol, such as adrenal steroids
`missing the C-19 methyl group, such as 19-nordeoxycorti-
`costerone and 19-norprogesterone (Wynne, Endocrinology
`107:1278-1280, 1980).
`
`

`

`US 7,361,646 B2
`
`9
`In general, the 11-beta side chain substituent, and par-
`ticularly the size of that substituent, can play a key role in
`determining the extent of a steroid’s antiglucocorticoid
`activity. Substitutions in the A ring of the steroid backbone
`can also be important. 17-hydroxypropenyl side chains
`generally decrease antiglucocorticoid activity in comparison
`to 17-propinyl side chain containing compounds.
`Additional glucocorticoid receptor antagonists known in
`the art and suitable for practice of the invention include
`21-hydroxy-6,19-oxidoprogesterone
`(see Vicent, Mol.
`Pharm. 52:749-753, 1997), Org31710 (see Mizutani, JSle—
`roid Biochem Mol Biol 42(7):695-704, 1992), RU43044,
`RU40555 (see Kim, JSleroid Biochem Mol Biol. 67(3):213-
`22, 1998), RU28362, and ZK98299.
`B. Non-Steroidal Anti-Glucocorticoids as Antagonists.
`Non-steroidal glucocorticoid antagonists are also used in
`the methods of the invention to gastroesophageal reflux
`disease in a subject. These include synthetic mimetics and
`analogs of proteins, including partially peptidic, pseudopep-
`tidic and non-peptidic molecular entities. For example,
`oligomeric peptidomimetics useful in the invention include
`(alpha-beta-unsaturated)
`peptidosulfonamides, N—substi-
`tuted glycine derivatives, oligo carbamates, oligo urea pep-
`tidomimetics, hydrazinopeptides, oligosulfones and the like
`(see, e.g., Amour, Int. J. Pept. Protein Res. 43:297-304,
`1994; de Bont, Bioorganic & Medicinal Chem. 4:667-672,
`1996). The creation and simultaneous screening of large
`libraries of synthetic molecules can be carried out using
`well-known techniques in combinatorial chemistry,
`for
`example, see van Breemen, Anal Chem 69:2159-2164, 1997;
`and Lam, Anticancer Drug Des 12: 145-167, 1997. Design of
`peptidomimetics specific for GR can be designed using
`computer programs
`in conjunction with combinatorial
`chemistry (combinatorial
`library)
`screening approaches
`(Murray, J. of Computer-Aided Molec. Design 9:381-395,
`1995; Bohm, J. ofCompuler-Aided Molec. Design 10:265-
`272, 1996). Such “rational drug design” can help develop
`peptide isomerics and conformers including cycloisomers,
`retro-inverso isomers, retro isomers and the like (as dis-
`cussed in Chorev, libTech 13:438-445, 1995).
`Examples of non-steroidal GR antagonists include keto-
`conazole,
`clotrimazole; N-(triphenylmethyl)imidazole;
`N—([2-fluoro-9-phenyl]fluorenyl)imidazole; N—([2-pyridyl]
`diphenylmethyl)imidazole;
`N—(2-[4,4',4"-trichlorotrityl]
`oxyethyl)morpholine; 1-(2[4,4',4"-trichlorotrityl]oxyethyl)-
`4-(2-hydroxyethyl)piperazine
`dimaleate;
`N—([4,4',4"] -
`trichlorotrityl)imidazole; 9-(3-mercapto-1,2,4-triazolyl)-9-
`phenyl-2,7-difluorofluorenone;
`1-(2-chlorotrityl) -3 ,5 -
`dimethylpyrazole;
`4-(morpholin