WO2009114516A1 - Therapy for disorders of the proximal digestive tract - Google Patents
Therapy for disorders of the proximal digestive tract Download PDFInfo
- Publication number
- WO2009114516A1 WO2009114516A1 PCT/US2009/036642 US2009036642W WO2009114516A1 WO 2009114516 A1 WO2009114516 A1 WO 2009114516A1 US 2009036642 W US2009036642 W US 2009036642W WO 2009114516 A1 WO2009114516 A1 WO 2009114516A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carboxy
- imidazol
- ethylamino
- medicament
- acid
- Prior art date
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to pharmacotherapy for inflammatory, erosive, dyspeptic and reflux disorders of the proximal digestive tract including esophagus, stomach and duodenum. More particularly, the invention relates to methods for managing or treating such disorders and for protecting mucosal surfaces of the proximal digestive tract from erosion or ulceration.
- the digestive tract also referred to as the alimentary canal (nourishment canal) or the gut, is part of the digestive system, i.e., the system of organs within multicellular animals which takes in food, digests it to extract energy and nutrients, and expels the remaining waste. This process is called digestion.
- the digestive tract includes those organs through which food or solid excreta pass in the course of the digestive process, but excludes those organs of the digestive system, adjacent to and connecting with the digestive tract, that store and/or secrete substances aiding in digestion, for example liver, gallbladder and pancreas.
- proximal digestive tract herein means that part of the digestive tract extending from esophagus to duodenum, comprising the esophagus (including the cardiac antrum and esophageal sphincter), stomach (including the cardia, corpus, pyloric antrum, pyloric canal, pylorus and pyloric sphincter) and duodenum (the proximal portion of the small intestine, including the duodenal bulb).
- the esophagus, stomach and duodenum have a mucosal lining (esophageal, gastric and duodenal mucosa respectively).
- disorders of the proximal digestive tract can be acute or chronic, and include inflammatory, erosive, dyspeptic and reflux disorders. These are not discrete classes of disorder, but overlap one another and in some cases have symptoms and/or etiological factors in common.
- Inflammation can be general to all or a major portion of the proximal digestive tract (and can extend to distal portions of the tract including jejunum, ileum and large intestine), or relatively localized, for example in the esophagus (esophag ⁇ tis), stomach (gastritis), pyloric antrum (antral gastritis), pylorus (pyloritis) or duodenum (duodenitis).
- Such inflammatory disorders can be acute or chronic and can arise from a variety of identifiable causes or can, in some cases, be idiopathic.
- the most common causal agent especially in gastritis (including antral gastritis and pyloritis) and duodenitis, is bacterial infection, the principal infective agent being the gram-negative bacillus Helicobacter pylori.
- Irritant agents including irritants in food, beverages and medications, can also precipitate inflammation.
- NSAIDs nonsteroidal anti-inflammatory drugs
- NSAIDs nonsteroidal anti-inflammatory drugs
- sprue also known as celiac sprue or celiac disease.
- inflammation of the mucosa is caused by a cascade of immune events, and is activated in predisposed individuals by exposure to certain proteins called gliadins (of which gluten is the most important) in cereal grains, particularly wheat, barley and oats.
- hiflammatory involvement has been identified in some cases of gastroparesis, a condition in which reduced muscle function prevents normal stomach emptying.
- Inflammation of the mucosal lining of the proximal digestive tract can lead to atrophy of the mucosa and parietal cells, particularly in the stomach (atrophic gastritis).
- Loss of gastric parietal cells, particularly in gastritis of autoimmune origin results in absence of a glycoprotein known as intrinsic factor essential for absorption of vitamin Bi 2 , leading to vitamin Bi 2 deficiency, manifesting as pernicious anemia.
- Peptic ulcer disease is a term generally given to erosive or ulcerative inflammation of the stomach and/or duodenum in which the normal mucosal protection from injurious effects of gastric fluid (principally gastric acid and pepsin) is diminished.
- gastric fluid principally gastric acid and pepsin
- Any of the causes of inflammation mentioned above can be involved, but again the most common causes include H. pylori infection and NSAID use. It has been estimated that 10-30% of patients on regular NSAID therapy develop gastric ulcers.
- Peptic ulcer disease can be further aggravated by various factors including diet, stress and tobacco use, and can be secondary to other diseases including chronic kidney disease, chronic obstructive pulmonary disease (COPD) and alcoholism.
- Peptic ulcers can bleed (hemorrhagic gastritis, hemorrhagic duodenitis) and in extreme cases can perforate the stomach or duodenal wall with potentially severe or Hfe-threatening consequences including peritonitis and sepsis.
- the term dyspepsia refers to symptoms originating in the proximal digestive tract, including pain and discomfort, often with feelings of early satiety, bloating, eructation, dysphagia, nausea and/or vomiting.
- dyspepsia The most common form of pain arising from dyspepsia is heartburn.
- dyspepsia The most common form of pain arising from dyspepsia is heartburn.
- the term "dyspeptic disorder” is used herein to refer to any disease or condition in which such symptoms are manifested, including inflammatory and/or erosive diseases as described above and gastroesophageal reflux disease (GERD), described below.
- GGID gastroesophageal reflux disease
- Peptic ulcers and GERD are especially well-known etiological factors in dyspepsia.
- inflammatory, erosive and reflux disorders do not necessarily give rise to dyspepsia; furthermore, dyspepsia can arise without involvement of inflammatory, erosive or reflux disorders.
- GERD GERD
- Symptoms including heartburn and acid regurgitation, tend to be exacerbated by ingestion of fatty foods and caffeine, and by recumbent position. Damage to the mucosal lining of the esophagus (reflux esophagitis) occurs in many cases, often leading to development of esophageal erosions or ulcers (erosive esophagitis). Such damage is visible by endoscopy and, if unchecked, can in some cases lead to a precancerous condition known as Barrett's esophagus and thence to esophageal cancer. Gastroesophageal reflux in the absence of visible injury to the esophageal mucosa is known as endoscopy-negative reflux disease or nonerosive reflux disease (NERD).
- endoscopy-negative reflux disease or nonerosive reflux disease
- dyspepsia was the third most common symptomatic reason for ambulatory care visits in 1997;
- duodenal ulcers are 1.5 times as common as gastric ulcers
- H pylori infection is an etiological factor (i.e., commonly in duodenitis, gastritis, peptic ulcer disease and dyspepsia related to these, but not in GERD or most cases of functional dyspepsia)
- treatment of proximal digestive tract disorders typically includes medication with one or more antibiotics.
- antibiotics are usually prescribed, for example (a) metronidazole or clarithromycin and (b) tetracycline or amoxicillin.
- the treatment regimen typically includes an antisecretory agent to inhibit gastric acid secretion.
- agents are of two main classes: proton-pump inhibitors (PPIs) such as omeprazole, lansoprazole or rabeprazole; and histamine H 2 -receptor antagonists such as cimetidine. famotidine and ranitidine. Older medications that neutralize excess acid in the stomach (antacids) can still be useful adjuncts.
- Other antiulcer medications include sucralfate and prostaglandins such as misoprostol.
- McCoIl (2000) Gastroenterol. 35(Suppl.
- H. j ⁇ /orf-negative ulcers for example NSAID-induced or idiopathic gastroduodenal ulcers
- H. pylori-positive ulcers reported that H. j ⁇ /orf-negative ulcers (for example NSAID-induced or idiopathic gastroduodenal ulcers) are more difficult to control with antisecretory drugs than H. pylori-positive ulcers.
- NF-KB nuclear factor KB
- Angiotensin II Ang II
- RAS renin-angiotensin system
- ACE angiotensin-converting enzyme
- Ang II In the classical pathway of Ang II synthesis in the circulating RAS, the precursor of Ang II is angiotensinogen, which is principally produced in the liver and then cleaved by renin to form angiotensin I (Ang I), which is converted by ACE into Ang II that is carried to various target cells via the circulatory system.
- Ang I angiotensin I
- ACE angiotensin I
- tissue-specific renin-angiotensin systems have been identified in many organs, suggesting that various tissues have the ability to synthesize Ang II independently of circulating RAS, including kidney, brain, aorta, adrenal gland, heart, stomach and colon.
- U.S. Patent No. 6,194,556 to Acton et al. discloses novel genes encoding ACE2. Therapeutics, diagnostics and screening assays based on these genes are also disclosed.
- Harmer et al (2002) FEBS Lett. 532:107-110 reported quantitative mapping of the transcriptional expression profile of ACE2 (and the two isoforms of ACE) in 72 human tissues. The study reportedly confirmed that ACE2 expression is high in renal and cardiovascular tissues. It was further reported that ACE2 shows comparably high levels of expression in the gastrointestinal system, in particular in ileum, duodenum, jejunum, cecum and colon.
- ACE2 activity appears to counterbalance inflammatory effects of Ang II in a variety of tissues, whether by increasing angiotensin (1-7) levels or reducing Ang II levels or both.
- U.S. Patent No. 6,900,033 to Parry et al discloses peptides comprising specific amino acid sequences that are said to specifically bind to ACE2 protein or ACE2-like polypeptides. It is proposed at column 53, lines 63-65 thereof that "an abnormally high angiotensin II level could result from abnormally low activity of ACE-2" and at column 63, lines 21-32 thereof that "ACE-2 binding polypeptides ... which activate ACE ⁇ 2-induced signal transduction can be administered to an animal to treat, prevent or ameliorate a disease or disorder associated with aberrant ACE-2 expression, lack of ACE-2 function, aberrant ACE-2 substrate expression, or lack of ACE-2 substrate function.
- ACE-2 binding polypeptides may potentiate or activate either all or a subset of the biological activities of ACE-2-mediated substrate action ."
- lines 40-43 thereof it is stated: "Since ACE-2 has been found to hydrolyze neurotensin ..., the invention provides for methods and compositions that can be used for digestive purposes.”
- line 44 - column 75, line 11 an extensive listing of disorders of the digestive system that "the invention” allegedly can be used to treat, prevent or ameliorate.
- ACE2 binding peptides that are reported to inhibit ACE2 in vitro are identified in Table 2 at columns 127TM 130 thereof.
- U.S. Patent No. 6,632,830 to Acton et al discloses compounds comprising a zinc coordinating moiety and an amino acid mimicking moiety, said to be useful for modulating activity of ACE2. More particularly, there are disclosed ACE2 inhibiting compounds of a generic formula presented therein. Such compounds are said to be useful for treating an "ACE-2 associated state" in a patient.
- ACE-2 associated states are said to include high blood pressure and diseases and disorders related thereto, in particular arterial hypertension, congestive heart failure, chronic heart failure, left ventricular hypertrophy, acute heart failure, myocardial infarction and cardiomyopathy; states associated with regulating smooth cell proliferation, in particular smooth muscle cell proliferation; kidney diseases and disorders; other hyperadrenergic states; kinetensin associated conditions including those caused by, or contributed to by, abnormal histamine release, for example in local or systemic allergic reactions including eczema, asthma and anaphylactic shock; infertility or other disorders relating to gamete maturation; cognitive disorders; disorders associated with bradykinin and des-Arg bradykinin; and "other examples” (column 36, lines 58-67 thereof) that are said to include "SIRS ..., sepsis, polytrauma, inflammatory bowel disease, acute and chronic pain, bone destruction in rheumatoid and osteo arthritis and periodontal disease, dysmenorrhea, premature
- a method for managing or treating an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract of a subject comprising administering to the subject a therapeutically effective amount of an ACE2 inhibitor.
- the disorder managed or treated comprises a condition other than chronic gastritis or Crohn's disease, for example at least one of duodenitis, acute gastritis, esophagitis, acute peptic ulcer, functional dyspepsia and gastroesophageal reflux disease (GERD).
- R 6 is hydroxyl or a protecting prodrug moiety
- R 7 is hydrogen, carboxylic acid, ether, alkoxy, an amide, a protecting prodrug moiety, hydroxyl, thiol, heterocyclyl, alkyl or amine;
- Q is CH 2 , O, NH or NR 3 , wherein R 3 is substituted or unsubstituted C 1-5 branched or straight chain alkyl, C 2 -. 5 branched or straight chain alkenyl, substituted or unsubstituted acyl, aryl or a C 3 -- 8 ring;
- G is a covalent bond or a CH 2 , ether, tbioether, amine or carbonyl linking moiety;
- M is heteroaryl, substituted with at least one subanchor moiety comprising a substituted or unsubstituted cycloalkyl or aryl ring, linked thereto through a sublmking moiety (CH 2 ) n or (CHb) n O(CBb) n where n is an integer from 0 to 3;
- J is a bond or a substituted or unsubstituted alkyl, alkenyl or alkynyl moiety;
- D is alkyl, alkenyl, alkynyl, aryl or heteroaryl, optionally linked to G or M to form a ring; for example the compound (S,S)-2-[l-carboxy-2-[3-(3 5 5-dichlorobenzyl)-3H-imidazol-4-yl]- ethylamino
- the disorder managed or treated comprises a condition other than chronic gastritis or Crohn's disease, for example at least one of duodenitis, acute gastritis, esophagitis, acute peptic ulcer, functional dyspepsia and GERD.
- a method for managing or treating an inflammatory, erosive, dyspeptic or reflux disorder that comprises at least one of duodenitis, duodenal ulcer, acute gastritis, acute gastric ulcer, esophagitis, esophageal ulcer, functional dyspepsia and GERD, the method comprising administering to the subject a therapeutically effective amount of an ACE2 inhibitor.
- a method for managing or treating an inflammatory, erosive, dyspeptic or reflux disorder that comprises at least one of duodenitis, duodenal ulcer, acute gastritis, acute gastric ulcer, esophagitis, esophageal ulcer, functional dyspepsia and GERD, the method comprising administering to the subject a therapeutically effective amount of a compound of formula
- a method for protecting from erosion or ulceration a mucosal surface of the proximal digestive tract of a subject at risk therefor comprising administering to the subject a therapeutically effective amount of an ACE2 inhibitor.
- an ACE2 inhibitor for example, can provide protection from duodenal, gastric and/or esophageal ulcer formation, development or recurrence related to concomitantly administered medication, e.g., comprising a nonsteroidal anti-inflammatory drug (NSAID).
- NSAID nonsteroidal anti-inflammatory drug
- such a method can, for example, provide protection from duodenal, gastric and/or esophageal ulcer formation, development or recurrence related to concomitantly administered medication, e.g., comprising an NSAID.
- a therapeutic combination comprising an NSAID in an anti-inflammatory, analgesic or antipyretic effective amount and an ACE2 inhibitor in an amount effective to protect mucosal surfaces of the proximal digestive tract from NS AID-induced erosion or ulceration.
- a therapeutic combination comprising an NSAID in an anti-inflammatory, analgesic or antipyretic effective amount and a gastroprotective agent in an amount effective to protect mucosal surfaces of the proximal digestive tract from NSAID-induced erosion or ulceration.
- the gastroprotective agent according to this embodiment comprises a compound of formula
- Fig. 1 is a schematic representation of enzymatic pathways of the renin- angiotensin system (RAS) involved in generation of angiotensin peptides. Key:
- ACE angiotensin converting enzyme
- AMP am ⁇ nopeptidase
- Ang angiotensin
- ATi angiotensin II type 1 receptor
- ATi_ 7 angiotensin (1-7) receptor
- IRAP insulin regulated am ⁇ nopept ⁇ dase
- NEP neutral endopeptidase 24.11
- PCP prolyl carboxypeptidase
- PEP prolyl endopeptidase.
- Fig. 2 is a graphical representation of inhibition by GL 1001 of in vivo basal NF- ⁇ B dependent transcription in recombinant reporter mice, as described in Example 2.
- Fig. 3 is a graphical representation of inhibition by GLlOOl of in vivo LPS induced
- mice were pretreated with GLlOOl
- mice (subcutaneous) for 1 hour before LPS treatment All mice treated with 0.1 mg/kg LPS (i.v.).
- Fig. 5 is a graphical representation of inhibition by GLlOOl of LPS induced NF- ⁇ B dependent transcription in selected organs of recombinant reporter mice, as described in Example 3. DETAILED DESCRIPTION
- ACE2 inhibitor having relatively high affinity for ACE2, as expressed for example by IC 50 or Ki, whether measured in vitro or in vivo, Jn one embodiment, the ACE2 inhibitor selected is one that exhibits in vitro an ACE2 IC 50 and/or an ACE2 KJ not greater than about 1000 nM, for example not greater than about 500 nM, not greater than about 250 nM, or not greater than about 10O nM.
- ACE2 inhibitors are known to differ not only in their affinity for ACE2 but also in their selectivity for binding to ACE2 as opposed to the more ubiquitous ACE.
- the ACE2 inhibitor exhibits selectivity for ACE2 versus ACE, as expressed by the ratio of IC S o(ACE) to IC 5 o(ACE2), of at least about 10 2 , for example at least about 10 3 , or at least about 10 4 .
- Peptide and non-pept ⁇ de ACE2 inhibitors can be used.
- Examples of peptide ACE2 inhibitors, and methods for preparing them, can be found for example in above-cited U.S. Patent No. 6,900,033, which is incorporated herein by reference in its entirety.
- Peptide compounds exhibiting relatively strong inhibition of ACE2 illustratively include those having peptide sequences identified as DX-512, DX-513, DX-524, DX-525, DX-529, DX-531, DX-599, DX-600, DX-601 and DX-602 in U.S. Patent No. 6,900,033.
- Antibodies that bind specifically to the ACE2 protein and thereby inhibit ACE2 activity can also be used in methods and compositions of the present invention.
- the ACE2 inhibitor comprises a non-peptide compound or a pharmaceutically acceptable salt thereof or a prodrug thereof.
- an ACE2 inhibitor can be of a type disclosed generically in above- cited U.S. Patent No. 6,632,830, which is incorporated herein by reference in its entirety, including any of the specific compounds disclosed therein along with methods of preparation thereof.
- the non-peptide compound comprises a zinc coordinating moiety and an amino acid mimicking moiety.
- non-peptide compound comprises a zinc coordinating moiety and an amino acid mimicking moiety to a subject having an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract.
- the non-peptide compound can be, but is not necessarily an ACE2 inhibitor. If such compound is an ACE2 inhibitor, it will be understood that any utility or benefit described herein for management or treatment of a proximal digestive tract disorder is not necessarily mediated by ACE2 inhibition.
- the present embodiment is not limited by any theory of mechanism of action proposed herein.
- non-peptide compound can have the formula
- R 6 is hydroxyl or a protecting prodrug moiety
- R 7 is hydrogen, carboxylic acid, ether, alkoxy, an amide, a protecting prodrug moiety, hydroxyl, thiol, heterocyclyl, alkyl or amine
- Q is CH 2 , O, NH or NR 3 , wherein R 3 is substituted or unsubstituted C]_ 5 branched or straight chain alkyl, C 2 - S branched or straight chain alkenyl, substituted or unsubstituted acyl, aryl or a C 3 - S ring;
- G is a covalent bond or a CH 2 , ether, thioether, amine or carbonyl linking moiety; M is heteroaryl, substituted with at least one subanchor moiety comprising a substituted or unsubstituted cycloalkyl or aryl ring, linked thereto through a sublinking moiety
- n is an integer from 0 to 3; J is a bond or a substituted or unsubstituted alkyl, alkenyl or alkynyl moiety; and D is alkyl, alkenyl, alkynyl, aryl or heteroaryl, optionally linked to G or M to form a ring.
- R 6 is hydroxyl
- R 7 is carboxylic acid
- Q is NH
- G is CH 2 .
- the heteroaryl group of M is imidazolyl, thienyl, triazolyl, pyrazolyl or thiazolyl
- the subanchor moiety according to this embodiment is
- C 3 ⁇ cycloalkyl phenyl, methylened ⁇ oxyphenyl, naphthalenyl, or phenyl having 1 to 3 substituents independently selected from halo, C M , alkyl, C 3 ⁇ cycloalkyl, trifluoromethyl,
- J is a bond or CH 2 moiety and D is C 1- ⁇ alkyl, C 3 ⁇ cycloalkyl or phenyl.
- R 6 is hydroxyl
- R 7 is carboxylic acid
- G is CH 2 ;
- M is imidazolyl, thienyl, triazolyl, pyrazolyl or thiazolyl, linked through a (CH 2 ),! or (CH 2 )O(CH 2 ) sublinking moiety, where n is an integer from 0 to 3, to a subanchor moiety that is C 3 _ 6 cycloalkyl, phenyl, methylenedioxyphenyl, naphthalenyl, or phenyl having 1 to 3 substituents independently selected from halo, Ci_ 6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, alkoxy, trifluoromethoxy, phenyl, cyano, nitro and carboxylic acid groups;
- J is a bond or CH 2 moiety
- D is C i_ 6 alkyl, C 3- ⁇ cycloalkyl or phenyl.
- the compound can be present in any enantiomeric configuration, e.g., (R 5 R), (R 5 S) 5 (S,R) or (S 5 S), or as a mixture, for example a racemic mixture, of enantiomers.
- the compound in general it is found preferable that the compound be present in the (S,S)-conf ⁇ guration.
- the compound is in the (S,S)-configuration and is substantially enantiomerically pure.
- the compound can exhibit an enantiomeric purity of at least about 90%, at least about 95%, at least about 98% or at least about 99%. by weight of all enantiomeric forms of the compound present.
- Illustrative compounds specifically disclosed in U.S. Patent No. 6,632,830 include the following, each of which can be in any enantiomeric form, illustratively in the (S,S)- configuration:
- any of the above compounds can be present in the above form or in the form of a pharmaceutically acceptable salt thereof, or a prodrug thereof.
- the present invention is illustrated herein by particular reference to (S,S)-2-[l- carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl]-ethylammo]-4-methylpentanoic acid, otherwise known as GLlOOl, which is the (S.S)-enantiomer of a compound having the formula
- this process comprises treating (S)-bistiduie methyl ester with BoC 2 O to provide a fully protected histidine derivative.
- the N-3 imidazole nitrogen is then selectively alkylated using the triflate of 3,5-dichlorobenzyl alcohol.
- GLlOOl a pharmaceutically acceptable salt or prodrug of GLlOOl can optionally be substituted for, or used in combination with, the free acid form of the drug, unless expressly indicated otherwise.
- NAAE N-(2-aminoethyl)-l-aziridxneethanamine
- Methods provided herein are useful in managing and treating inflammatory, erosive, dyspeptic and/or reflux disorders of the whole or any part or parts of the proximal digestive tract of a subject.
- Such disorders include, without limitation:
- Gastroduodenal ulcer refers to an erosive or ulcerative condition present in both stomach and duodenum.
- the disorder managed or treated is other than chronic gastritis or Crohn's disease.
- the terms “treat,” “treating” or “treatment” herein include preventive or prophylactic use of an agent in a subject at risk of, or having a prognosis including, an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract, as well as use of such an agent in a subject already experiencing such a disorder, as a therapy to alleviate, relieve, reduce intensity of or eliminate one or more symptoms of the disorder or an underlying cause thereof.
- treatment includes (a) preventing a disorder from occurring in a subject that may be predisposed to the disorder but in whom the disorder has not yet been diagnosed; (b) inhibiting progression of the disorder, including arresting its development; and/or (c) relieving, alleviating or ameliorating the disorder, or primary or secondary signs and symptoms thereof, including promoting, inducing or maintaining remission of the disorder.
- the terms "prevent,” “preventing,” “prevention” and “preventive” will be understood to have their normal meaning in the medical arts of reducing risk or future incidence or severity of a disorder, or of one or more symptoms thereof, as opposed to total elimination of future occurrence of the disorder or symptoms.
- a method for protecting from erosion or ulceration a mucosal surface of the proximal digestive tract of a subject at risk therefor comprising administering to the subject a therapeutically effective amount of an ACE2 inhibitor or a compound of formula
- a method for promoting healing of mucosal ulceration in a subject having an inflammatory or erosive disorder of the proximal digestive tract comprising administering to the subject a therapeutically effective amount of an ACE2 inhibitor or a compound of formula
- such a method can promote healing of duodenal, gastric and/or esophageal ulcers arising from any cause including but not limited to concomitantly administered medication, e.g., comprising an NSAID.
- a method for maintaining remission of mucosal ulceration in a subject having an inflammatory or erosive disorder of the proximal digestive tract comprising administering to the subject a therapeutically effective amount of an ACE2 inhibitor or a compound of formula
- Such a method can maintain remission from duodenal, gastric and/or esophageal ulcers arising from any cause including but not limited to concomitantly administered medication, e.g., comprising an NSAID.
- "Maintaining remission” herein means extending or prolonging a period of remission between healing of an ulcer and re-formation of an ulcer at the same or a different locus in the proximal digestive tract.
- the compound can be administered in monotherapy or in combination or adjunctive therapy with another agent for management or treatment of an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract, including any such disorder illustratively listed above.
- an embodiment of the invention comprises administering, in combination or adjunctive therapy, to a subject having or at risk of such a disorder (a) an ACE2 inhibitor or a compound of formula
- a second agent for management or treatment of the disorder in therapeutically effective absolute and relative amounts. It will be recognized that what constitutes a therapeutically effective amount of a drug in combination or adjunctive therapy may differ from that in monotherapy, having regard to possible adverse interactions between drugs, co-action of drugs having different modes of action, etc.
- drugs suitable as the second agent include, without limitation, PPIs, e.g., omeprazole (or its S-enantiomer esomeprazole), lansoprazole, pantoprazole or rabeprazole; H 2 receptor antagonists, e.g., cimetidine, famotidine or ranitidine; antacids, e.g., bismuth subsalicylate; prostaglandins, e.g., misoprostol; sucralfate; and, in the case of H.
- PPIs e.g., omeprazole (or its S-enantiomer esomeprazole), lansoprazole, pantoprazole or rabeprazole
- H 2 receptor antagonists e.g., cimetidine, famotidine or ranitidine
- antacids e.g., bismuth subsalicylate
- prostaglandins e
- antibiotics e.g., amoxicillin, clarithromycin, metronidazole or tetracycline.
- Multiple combination therapies including three or more drugs are also contemplated, for example GLlOOl + rabeprazole + metronidazole + amoxicillin.
- GLlOOl GLlOOl
- a subject having an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract that is refractory to PPI or H 2 receptor antagonist treatment is administered to a subject having an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract that is refractory to PPI or H 2 receptor antagonist treatment.
- Such administration can be in monotherapy or in combination or adjunctive therapy as described above.
- a "subject" herein is a warm-blooded animal, generally a mammal such as, for example, a cat, dog, horse, cow, pig, mouse, rat or primate, including a human.
- the subject is human, for example a patient having a clinically diagnosed inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract such as any of those illustratively listed above.
- Animal models in experimental investigations relevant Io human disease are also examples of "subjects" herein, and can include for example rodents ⁇ e.g., mouse, rat, guinea pig), lagomorphs ⁇ e.g., rabbit), carnivores ⁇ e.g., cat, dog), or nonhuman primates ⁇ e.g., monkey, chimpanzee). Further, the subject can be an animal (for example a domestic, farm, working, sporting or zoo animal) in veterinary care.
- Certain compounds useful according to the present invention have acid and/or base moieties that, under suitable conditions, can form salts with suitable acids.
- GLlOOl has two acid moieties that, under suitable conditions, can form salts with suitable bases, and an amino group that, under suitable conditions, can form salts with suitable acids.
- Internal salts can also be formed.
- the compound can be used in its free acid/base form or in the form of an internal salt, an acid addition salt or a salt with a base.
- Acid addition salts can illustratively be formed with inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acids or hydrohalic ⁇ e.g., hydrochloric or hydrobromic) acids; with organic carboxylic acids such as (a) C 1-4 alkanecarboxylic acids which may be unsubstituted or substituted ⁇ e.g., halosubstituted), for example acetic acid, (b) saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acids, (c) hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acids, (d) amino acids, for example aspartic or glutamic acids, or (e) benzoic acid; or with organic sulfonic acids such as C 1 - 4 alkanesulfonic acids or arylsulfonic
- Salts with bases include metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts; or salts with ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkyl amine, for example ethylamine, tert-butylamine, diethylamine, diisopropylamitie, triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or tri-(hydroxy lower alkyl) amine, for example monoethanolamine, diethanolamine or triethanolamine.
- metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts
- salts with ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower al
- a prodrug of the compound or a salt of such prodrug can be used.
- a prodrug is a compound, typically itself having weak or no pharmaceutical activity, that is cleaved, metabolized or otherwise converted in the body of a subject to an active compound.
- Examples of prodrugs are esters, particularly alkanoyl esters and more particularly C 1 - ⁇ alkanoyl esters. Other examples include carbamates, carbonates, ketals, acetals, phosphates, phosphonates, sulfates and sulfonates.
- Various prodrugs of GLlOOl, and methods of making such prodrugs are disclosed, for instance, in above-referenced U.S. Patent No. 6,632,830 and U.S. Published Patent Application No. 2004/0082496.
- the agent in question is used in the form of the compound (as free base or free acid) or a pharmaceutically acceptable salt thereof.
- the compound should be administered in a therapeutically effective amount. What constitutes a therapeutically effective amount depends on a number of factors, including the particular subject's age and body weight, the nature, stage and severity of the disease, the particular effect sought (e.g., reduction of inflammation, alleviation of symptoms, healing of ulcers, maintenance of remission, etc.) and other factors, but for most subjects a dosage amount of about 0.5 to about 5000 mg/day, more typically about 5 to about 2000 mg/day, will be found suitable.
- the dosage employed is about 10 to about 1800 mg/day, about 50 to about 1600 mg/day or about 100 to about 1500 mg/day; illustratively about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 60O 5 about 650, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500 or about 1600 mg/day.
- a method of the invention comprises administering to the subject an ACE2 inhibitor or a compound of formula
- GLlOOl in an amount of about 0.5 to about 5000 mg/day, for example about 5 to about 2000 mg/day, about 10 to about 1800 mg/day, about 50 to about 1600 mg/day or about 100 to about 1500 mg/day; illustratively about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500 or about 1600 mg/day.
- the above dosages are given on a per diem basis but should not be interpreted as necessarily being administered on a once daily frequency.
- the compound, or salt or prodrug thereof can be administered at any suitable frequency, for example as determined conventionally by a physician taking into account a number of factors, but typically about four times a day, three times a day, twice a day, once a day, every second day, twice a week, once a week, twice a month or once a month.
- the compound, or salt or prodrug thereof can alternatively be administered more or less continuously, for example by parenteral infusion in a hospital setting.
- a single dose may be administered, but more typically administration is according to a regimen involving repeated dosage over a treatment period.
- the daily dosage and/or frequency of administration can, if desired, be varied over the course of the treatment period, for example introducing the subject to the compound at a relatively low dose and then increasing the dose in one or more steps until a full dose is reached.
- the treatment period is generally as long as is needed to achieve a desired outcome, for example induction or maintenance of remission, alleviation of symptoms, healing of ulcers, etc.
- a desired outcome for example induction or maintenance of remission, alleviation of symptoms, healing of ulcers, etc.
- intermittent administration can be timed, for example, to correspond to flares of the disorder.
- Administration can be by any suitable route, including without limitation oral, buccal, sublingual, intranasal, intraocular, rectal, vaginal, transdermal or parenteral (e.g., intradermal, subcutaneous, intramuscular, intravenous, intra-arterial, intratracheal, intraventricular, intraperitoneal, etc.) routes, and including by inhalation or implantation.
- parenteral e.g., intradermal, subcutaneous, intramuscular, intravenous, intra-arterial, intratracheal, intraventricular, intraperitoneal, etc.
- API active pharmaceutical ingredient
- the excipient(s) collectively provide a vehicle or carrier for the API.
- Pharmaceutical compositions adapted for all possible routes of administration are well known in the art and can be prepared according to principles and procedures set forth in standard texts and handbooks such as those individually cited below.
- the API in a liquid formulation suitable, for example, for parenteral, intranasal or oral delivery, can be present in solution or suspension, or in some other form of dispersion, in a liquid medium that comprises a diluent such as water.
- additional excipients that can be present in such a formulation include a tonicifying agent, a buffer (e.g., a tris, phosphate, imidazole or bicarbonate buffer), a dispersing or suspending agent and/or a preservative.
- a parenteral formulation can be prepared in dry reconstitutable form, requiring addition of a liquid carrier such as water or saline prior to administration by injection.
- the API can be present in dispersed form in a suitable liquid
- semi-solid e.g., as a cream or ointment
- solid e.g., as a suppository
- the medium can be hydrophilic or lipophilic.
- the API can be formulated in liquid or solid form, for example as a solid unit dosage form such as a tablet or capsule.
- a dosage form typically comprises as excipients one or more pharmaceutically acceptable diluents, binding agents, disintegrants, wetting agents and/or ant ⁇ frictional agents (lubricants, anti-adherents and/or glidants).
- excipients have two or more functions in a pharmaceutical composition. Characterization herein of a particular excipient as having a certain function, e.g., diluent, binding agent, disintegrant, etc., should not be read as limiting to that function.
- Suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; lactitol; maltitol; mannit ⁇ l; sorbitol; xylitol; dextrose and dextrose monohydrate; fructose; sucrose and sucrose-based diluents such as compressible sugar, confectioner's sugar and sugar spheres; maltose; inositol; hydrolyzed cereal solids; starches (e.g., com starch, wheat starch, rice starch, potato starch, tapioca starch, etc.), starch components such as amylose and dextrates, and modified or processed starches such as pregelati ⁇ ized starch; dextrins; celluloses including powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, food grade sources of ⁇ - and amorphous cellulose and powdere
- Such diluents typically constitute in total about 5% to about 99%, for example about 10% to about 85%, or about 20% to about 80%, by weight of the composition.
- the diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
- Lactose, microcrystalline cellulose and starch are particularly useful diluents.
- Binding agents or adhesives are useful excipients, particularly where the composition is in the form of a tablet. Such binding agents and adhesives should impart sufficient cohesion to the blend being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
- Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; glucose; polydextrose; starch including pregelatinized starch; gelatin; modified celluloses including methylcellulose, carmellose sodium, hydroxypropylmethylcellulose (HPMC or hypromellose), hydroxypropyl- cellulose, hydroxyethylcellulose and ethylcellulose; dextrins including maltodextrin; zein; alginic acid and salts of alginic acid, for example sodium alginate; magnesium aluminum silicate; bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum; polysaccharide acids; polyvinylpyrrolidone (povidone), for example povidone K-15, K-30 and K-29/32; polyacrylic acids (carbomers); polymethacrylates; and the like.
- binding agents and/or adhesives typically constitute in total about 0.5% to about 25%, for example about 0.75% to about 15%, or about 1% to about 10%, by weight of the composition.
- Povidone is a particularly useful binding agent for tablet formulations, and, if present, typically constitutes about 0.5% to about 15%, for example about 1% to about 10%, or about 2% to about 8%, by weight of the composition.
- Suitable disintegrants include, either individually or in combination, starches including pregelatinized starch and sodium starch glycolate; clays; magnesium aluminum silicate; cellulose-based disintegrants such as powdered cellulose, microcrystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium and croscarmellose sodium; alginates; povidone; crospovidone; polacrilin potassium; gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums; colloidal silicon dioxide; and the like.
- One or more disintegrants, if present, typically constitute in total about 0.2% to about 30%, for example about 0.2% to about 10%, or about 0.2% to about 5%, by weight of the composition.
- Croscarmellose sodium and crospovidone are particularly useful disintegrants for tablet or capsule formulations, and, if present, typically constitute in total about 0.2% to about 10%, for example about 0.5% to about 7%, or about 1% to about 5%, by weight of the composition.
- wetting agents are normally selected to maintain the drug or drugs in close association with water, a condition that is believed to improve bioavailability of the composition.
- surfactants that can be used as wetting agents include, either individually or in combination, quaternary ammonium compounds, for example benzalkor ⁇ um chloride, benzethonium chloride and cetylpyridinium chloride; dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers); polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example ceteth-10, la
- wetting agents that are anionic surfactants are particularly useful.
- sodium lauryl sulfate if present, typically constitutes about 0.25% to about 7%, for example about 0.4% to about 4%, or about 0,5% to about 2%, by weight of the composition.
- Lubricants reduce friction between a tableting mixture and tableting equipment during compression of tablet formulations.
- Suitable lubricants include, either individually or in combination, glyceryl behenate; stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and the like.
- One or more lubricants typically constitute in total about 0.05% to about 10%, for example about 0.1% to about 8%, or about 0.2% to about 5%, by weight of the composition.
- Magnesium stearate is a particularly useful lubricant.
- Anti-adherents reduce sticking of a tablet formulation to equipment surfaces. Suitable anti-adherents include, either individually or in combination, talc, colloidal silicon dioxide, starch, DL-leucine, sodium lauryl sulfate and metallic stearates.
- One or more anti- adherents, if present typically constitute in total about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 2%, by weight of the composition.
- Glidants improve flow properties and reduce static in a tableting mixture.
- Suitable glidants include, either individually or in combination, colloidal silicon dioxide, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate and metallic stearates.
- One or more glidants, if present, typically constitute in total about 0.1% to about 10%, for example about 0.1% to about 5%, or about 0.1% to about 2%, by weight of the composition.
- Talc and colloidal silicon dioxide are particularly useful anti-adherents and glidants.
- compositions useful herein typically contains the compound or salt or prodrug thereof in an amount of about 1% to about 99%, more typically about 5% to about 90% or about 10% to about 60%, by weight of the composition.
- a unit dosage form such as a tablet or capsule can conveniently contain an amount of the compound providing a single dose, although where the dose required is large it may be necessary or desirable to administer a plurality of dosage forms as a single dose.
- a unit dosage form can comprise the compound in an amount of about about 10 to about 1800 mg, for example about 50 to about 1600 mg or about 100 to about 1500 mg; illustratively about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650. about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500 or about 1600 mg.
- ACE2 inhibitor on the renin-angiotensin system (RAS) might be predicted to involve increase in level of Ang II (see Fig. 1), which, as indicated above is implicated in a variety of pro-inflammatory effects.
- the present inventors have found, contrary to such prediction, that activation of NF-KB, a key mediator for synthesis of proinflammatory cytokines, is not promoted but inhibited by the ACE2 inhibitor.
- NF-KB a key mediator for synthesis of proinflammatory cytokines
- the ACE2 inhibitor GLlOOl inhibits in vivo basal NF- ⁇ B dependent transcription in recombinant reporter mice. This finding is reported in greater detail in Example 2 below, and appears to support an antiinflammatory effect of the ACE2 inhibitor that is contrary to expectation based on present understanding of the role of ACE2 in the RAS.
- ACE2 mRNA expression in tissues of the digestive tract is especially strongly elevated in chronic gastritis. It is accordingly contemplated that elevation of ACE2 in chronic gastritis is a potential pathogenic factor in that disease and that administration of an ACE2 inhibitor such as GLlOOl is beneficial in treatment of chronic gastritis. Confirmation of the effectiveness of GLlOOl in a chronic gastritis model is seen in Example 4 below. This finding is especially surprising in view of studies reported in the literature (e.g., Fleichman et al.
- Ang II the level of which would be expected to increase following treatment with an ACE2 inhibitor
- lowering of Ang II for example with the ACE inhibitor enalapril, promotes healing of gastric mucosal erosions.
- other inflammatory, erosive, dyspeptic and reflux disorders of the proximal digestive tract including acute gastritis, acute or chronic duodenitis, acute or chronic esophagitis, duodenal ulcer, celiac sprue, functional dyspepsia and GERD, can be similarly responsive to an ACE2 inhibitor such as GLlOOl.
- GLlOOl is shown to provide gastroprotect ⁇ on from acute NSAID toxicity.
- gastroprotection will be understood herein to extend to protection not only of the stomach but also of other parts of the digestive tract including the duodenum from NSAID-induced mucosal injury.
- a disorder especially an inflammatory or erosive disorder, extends to more distal parts of the digestive tract, as in the case, for example, of celiac sprue, or NSAID-induced injury to the intestinal tract (NSAID enteropathy), an ACE2 inhibitor or a compound of formula
- GLlOOl can have therapeutic benefit likewise extending to such more distal parts.
- therapeutic combination refers to a plurality of agents that, when administered to a subject together or separately, are co-active in bringing therapeutic benefit to the subject. Such administration is referred to as “combination therapy,” “co-therapy,” “adjunctive therapy” or “add-on therapy.”
- one agent can potentiate or enhance the therapeutic effect of another, or reduce an adverse side effect of another, or one or more agents can be effectively administered at a lower dose than when used alone, or can provide greater therapeutic benefit than when used alone, or can complementarity address different aspects, symptoms or etiological factors of a disease or condition.
- a therapeutic combination comprising an ACE2 inhibitor or a compound of formula
- such a combination can be useful to treat an inflammatory, erosive, dyspeptic or reflux disorder of the proximal digestive tract.
- a therapeutic combination comprising an
- NSAID and a gastroprotective agent that comprises an ACE2 inhibitor or a compound of formula
- NSAID as defined above, e.g., GLlOOl.
- a combination can be useful to treat any disease or condition in which an NSAID is indicated, for example inflammatory diseases such as rheumatoid arthritis and osteoarthritis, musculoskeletal pain, etc.
- the NSAID is present in an anti-inflammatory, analgesic or antipyretic effective amount, and the gastroprotective agent is present in an amount effective to protect mucosal surfaces of the proximal digestive tract from erosion or ulceration induced by the NSAID.
- Nonlimiting examples of NSAIDs useful in such a combination include salicylic acid derivatives (such as salicylic acid, acetylsalicylic acid, methyl salicylate, difiunisal, olsalazine, salsalate and sulfasalazine), indole and indene acetic acids (such as ⁇ ndomethacin, etodolac and sulindac), fenamates (such as etofenamic, meclofenamic, mefenamic, flufenamic, niflumic and tolfenamic acids), heteroaryl acetic acids (such as acemetacin, alclofenac, clidanac, diclofenac, fenchlofenac, fentiazac, furofenac, ibufenac, isoxepac, ketorolac, oxipinac, tiopinac, tolmetin,
- COX-2 selective inhibitors are also considered as NSAIDs. These typically are less damaging to the proximal digestive tract mucosa than nonselective NSAIDs, but may still benefit from gastroprotection according to the present invention.
- Nonlimiting examples of COX-2 selective inhibitors include celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, 2-(3 ,5 -difluorophenyl)-3 -[4-(methylsulfonyl)phenyl] -2-cyclopenten- 1 - one, (S)-6,8"dichloro-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid, 2-(3,4-difluoro- phenyl)-4-(3-hydroxy-3-methyl-l-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)
- the therapeutic combination comprises GLlOOl and at least one NSAID selected from acetylsalicylic acid (aspirin), indomethacin, diclofenac, ibuprofen, naproxen, oxaprozin, meloxicam and celecoxib.
- NSAID selected from acetylsalicylic acid (aspirin), indomethacin, diclofenac, ibuprofen, naproxen, oxaprozin, meloxicam and celecoxib.
- the two or more active agents administered in combination or adjunctive therapy can be formulated in one pharmaceutical preparation (single dosage form) for administration to the subject at the same time, or in two or more distinct preparations (separate dosage forms) for administration to the subject at the same or different times, e.g., sequentially.
- the two distinct preparations can be formulated for administration by the same route or by different routes.
- kits comprising, in a first container, a first agent that comprises an ACE2 inhibitor or a compound of formula
- the first and second agents are separately packaged and available for sale independently of one another, but are co-marketed or co- promoted for use according to the invention.
- the separate dosage forms may also be presented to a subject separately and independently, for use according to the invention.
- the first and second agents may be administered on the same or on different schedules, for example on a daily, weekly or monthly basis.
- Example 1 ACE2 mRNA expression in normal and disease states
- ACE2 mRNA expression has now been examined in various human tissues from normal and diseased subjects, using the BioExpress® System.
- This system includes mRNA expression data from about 18,000 samples, of which about 90% are from human tissues, comprising both normal and diseased samples from about 435 disease states.
- human tissue samples either from surgical biopsy or post-mortem removal, were processed for mRNA expression profile analysis using Affymetrix GeneChips®. Each tissue sample was examined by a board-certified pathologist to confirm pathological diagnoses.
- RNA isolation, cDNA synthesis, cRNA amplification and labeling, hybridizations, and signal normalization were carried out using standard Affymetrix protocols. Computational analysis was performed using Genesis Enterprise System® Software and the Ascenta® software system.
- Table 1 also shows that four of the top five highest expression levels of ACE2 mRNA in normal human tissues (other than heart, kidney and testis) were in components of the gastrointestinal tract, namely (in descending order of expression level): duodenum, small intestine, colon and stomach. Table 1. Relative ⁇ evels of ACE2 mRNA expression in normal tissues
- ACE2 mRNA expression in disease states encompassed by the B ⁇ oExpress® System showed elevation of ACE2 mRNA in only a few conditions, mainly inflammatory conditions of components of the gastrointestinal tract.
- Table 2 shows that ACE2 mRNA expression was elevated (in descending order of average fold change vs. normal) in inflammatory conditions of the stomach (chronic gastritis), major salivary gland (excluding parotid) (chronic sialadenitis), and colon (Crohn's disease, active (chronic or acute inflammation)).
- ACE2 mRNA levels were not elevated in colon with ulcerative colitis or small intestine with Crohn's disease, the already substantial levels of such mRNA in normal colon and small intestine suggest at least that ACE2 activity is present and, therefore, could still constitute a pathogenic factor in these two diseased tissues.
- Example 2 Inhibition by GLlOQl of in vivo basal NF- ⁇ B dependent transcription in recombinant reporter mice
- inflammation is likely to depend, at least in part, on activation and nuclear translocation of NF- ⁇ B family members. See, e.g., Fichtner- Feigl et al. (2005) J. Clin. Invest. 115:3057-3071 and sources cited therein.
- ThI- rned ⁇ ated inflammations dependent on IL- 12 and/or IL-23 synthesis of these cytokines is regulated by NF- ⁇ B transcription factors.
- Th2-mediated inflammations dependent on IL-4 or IL- 13 synthesis of these cytokines is also dependent on NF- ⁇ B transcription factors, albeit more indirectly than that of IL- 12 and IL-23.
- one method of treating the inflammation can be to administer agents that inhibit NF-icB activity, and indeed Fichtner-Feigl et al (2005), supra, have shown that NF- ⁇ B decoy oligodeoxynucleotides (ODNs) that prevent NF- ⁇ B activation of gene expression are effective in treating and preventing various models of ThI- and Th2-mediated inflammatory bowel disease in mice, including acute trinitrobenzene sulfonic acid (TNBS) induced colitis, as assessed by clinical course and effect on ThI cytokine production; chronic TNBS induced colitis, inhibiting both production of IL-23 /IL- 17 and development of fibrosis; and oxazolone-induced colitis, a Th2-mediated inflammatory process.
- TNBS acute trinitrobenzene sulfonic acid
- GLlOOl was tested for in vivo anti-inflammatory activity by examining its effects on basal levels of NF- ⁇ B dependent transcription in mice engineered in the germline with a construct containing an NF- ⁇ B enhancer linked to a luciferase gene (i.e., NF- ⁇ B::Luc mice), such that this NF- ⁇ B reporter construct is present in all cells of the mice.
- transgenic NF- ⁇ cB::Luc mice were generated using three NF- ⁇ B response elements from the Ig ⁇ light chain promoter fused to a firefly luciferase gene as described by Carlsen et al (2002) J. Immunol. 168:1441-1446.
- NF- ⁇ B::Luc mice were injected intraperitoneally with luciferin (150 mg/kg) 10 minutes before imaging, anesthetized (using 1-3% isoflurane) and placed into a light-tight camera box. Mice were imaged for up to two minutes from the dorsal or ventral aspects at high-resolution settings with a field of view of 20 cm.
- the light emitted from the transgene was detected by an IVIS® Imaging System 200 Series (Xenogen Corporation, Alameda, CA), digitized and displayed on a monitor.
- the Living Image® software (Xenogen Corporation, Alameda, CA; see Rice et al. (2002) J, Biomed. Opt. 6:432-440) displays data from the camera using a pseudocolor scale with colors representing variations of signal intensity. Signal data were also quantitated and archived using the Living Image® software. Photons of light were quantitated using an oval region of interest (ROI) of varying sizes depending on the procedure, as described further below.
- ROI oval region of interest
- luciferase assays organs were extracted and snap-frozen in liquid nitrogen. All tissue samples were placed in lysis buffer with inhibitors (Passive Lysis Buffer (Promega) and Complete Mini Protease Inhibitor Cocktail (Roche, Indianapolis, IN)), and were homogenized using a Handishear hand-held tissue homogenizer (VirTis, Gardiner, NY). Tissue homogenates were centrifuged and clarified lysates were used for lum ⁇ nometer assays and western blots. For the luminometer assays, Luciferase Assay Substrate (Luciferase Assay System, Promega) was prepared as indicated by the manufacturer and placed in disposable cuvettes.
- Luciferase Assay Substrate Luciferase Assay Substrate (Luciferase Assay System, Promega) was prepared as indicated by the manufacturer and placed in disposable cuvettes.
- Tissue homogenates (20 ⁇ l) and substrate (100 ⁇ l) were mixed and measurements were taken in a Veritas Microplate Luminometer (Turner Designs, Sunnyvale, CA) with the parameters of a 2-second delay, 10-second. Background luminescence readings were obtained and the background readings were subtracted from the luminescent data. Protein concentrations were determined using the BCA Protein Assay Kit (Pierce, Rockford, IL) following the manufacturer's protocols and analyzed using a VERS Amax tunable microplate reader and associated Softmax Pro version 3.1.2 software (Molecular Devices, Sunnyvale CA). The luminescence for each of the protein lysates was calculated as arbitrary units of light per microgram of protein. Statistical analyses include MEAN, SEM and ANOVA and Student's t-test between treatment groups.
- Example 3 GLlOOl inhibits in vivo LPS-induced NF- ⁇ B dependent transcription in recombinant reporter mice
- Bacterial Hpopolysaccharide a major component of the cell wall of gram- negative bacteria, is a highly biologically active molecule which stimulates macrophages to produce and release TNF ⁇ . See, e.g., Jersmann et al. (2001) Infection and Immunity 69(3): 1273-1279, and sources cited therein.
- One of the recognized associations of bacterial infection with cardiovascular events is activation of endothelium and up-regulat ⁇ on of adhesion molecules.
- GLlOOl was further tested for in vivo anti-inflammatory activity by examining its effects on bacterial LPS-induced NF- ⁇ B dependent transcription in NF- ⁇ B::Luc mice.
- inflammation was induced in these mice at 6—10 weeks of age by administration of 0.5 mg/kg (i.v.) soluble LPS (sLPS; Sigma) one hour after administration of GLlOOl.
- Mice were subjected to quantitative abdominal imaging at 2, 4 and 6 hours following LPS administration, as described above.
- animals were euthanized and tissues were collected and preserved for further analysis. Luciferase signal was quantitated from several regions of interest.
- Statistical analyses include MEAN, SEM and ANOVA and Student's t-test between treatment groups.
- Example 4 GLlOQl promotes gastric ulcer healing in a rat model
- Example 5 GLlOOl inhibits acute indomethacin-induced gastric toxicity in a rat model [0165] A study was conducted to determine whether GLlOOl would inhibit acute NSAID (indomethacin)-induced gastric toxicity in a rat model (Wallace et al. (1998) Gastroenterol. 115:101-109). Several modes of treatment with GLlOOl or vehicle were employed, which included administration via drinking water, oral administration and subcutaneous administration as shown in Table 4.
- Myeloperoxidase is an enzyme found in all cells of myeloid origin, but particularly enriched within neutrophils. It is therefore used as a biochemical marker of granulocyte infiltration into tissue.
- Each group consisted of 6 rats.
- As a negative control one group received vehicle pretreatments (in the drinking water and by oral gavage) and then received vehicle instead of indomethacin.
- a positive control group received 100 ⁇ g/kg PGE 2 (Cayman Chemical) orally 30 minutes prior to administration of indomethacin, since this has previously been shown to markedly reduce the severity of indomethacin-induced gastric damage (see for example Robert et al (1979) Gastroenterol. 77:761-767).
- Vl 0.1 M citrate buffer
- V2 15% hydroxypropyl ⁇ -cyclodextrin
- V3 5% sodium bicarbonate
- indomethacin resulted in formation of hemorrhagic erosions in the corpus of the stomach.
- mean gastric damage scores varied from 20 to 54 (Table 5).
- Administration of GLlOOl both in drinking water and by oral gavage resulted in a significant reduction of severity of indomethacin-induced gastric damage (Group C vs. Group D; p ⁇ 0.01). It should be noted that the amount of consumption of water by the rats receiving GLlOOl in drinking water fell below what was anticipated, so the actual amount of the drug that was delivered was only 500-750 mg/kg/day rather than 1200 mg/kg/day as planned.
- indomethacin produced extensive gastric damage in all vehicle- pretreated groups.
- Pretreatment with PGE 2 the positive control, produced a significant reduction in the extent of indomethacin-induced gastric damage.
- Pretreatment with GLlOOl also produced a significant reduction of the severity of indomethacin-induced gastric damage, an effect that was dependent on the route of administration. In both circumstances in which GLlOOl was administered orally (i.e., alone or also via drinking water), this drug was effective. No significant effect was seen when it was administered in the drinking water alone or subcutaneously + drinking water.
- Example 6 GLlOOl inhibits acute diclofenac-induced gastric toxicity in a rat model
- one group received vehicle prelreatment, and then received vehicle instead of diclofenac.
- a positive control group received PGE 2 100 ⁇ g/kg orally, 30 minutes prior to administration of diclofenac.
- Treatments are summarized in Table 6. All treatments were administered by oral gavage. [0175] Three hours after diclofenac treatment, all animals were sacrificed and stomachs were removed and imaged to determine the severity of gastric damage. Additionally, stomach tissue samples were taken to assess disease activity and pharmacodynamic effects. Gastric damage scores were determined from photographic images (Ma & Wallace (2003) Am. J. Physiol. Gastrointest. Liver Physiol. 279:341-346).
- Removed stomachs were opened along the greater curvature, pinned out on a wax block, and photographed along a 25 mm ruler reference with a digital 35 mm camera.
- the lesion area was then determined using enlarged images and computer software (www.scioncorp.com/pages/scion image wmdows.htm) that allows superimposed drawing of the perimeter of a wound and calculation of the area based on the ruler reference.
- Stomach samples (excluding forestomach) were used for measurements of PGE 2 concentration, MPO activity and ACE2 activity.
- PGE 2 determinations are used in this study as a biomarker of diclofenac effect since its mechanism of action involves inhibition of cyclooxygenase (COX-2 and COX-I) enzymes which in turn results in inhibition of PGE 2 synthesis.
- Concentration of PGE 2 from stomach tissue samples was performed as described by Souza et al (2003), supra, and quantification was obtained by LC- MS.
- MPO 5 an enzyme found in abundance in granulocytes, is used as a biochemical marker of tissue inflammation. When tissues undergo inflammatory processes, granulocytes are recruited to the site of inflammation and infiltrate the affected tissue giving rise to increase MPO activity (Souza et al (2003), supra).
- the ACE2 activity assay is similar to the method of Vickers et al (2002) J. Biol. Chem. 277:14838-14843, wherein purified recombinant ACE2 (100 pM) and a quenched fluorescent substrate (100-150 ⁇ M APK (7-methoxycoumarin-4-yl)acetyl-Ala-Pro- Lys (2,4-dinitrophenyl)) are used in end-point fluorescence reactions (excitation 320 nm, emission 405 nm).
- ACE2 For stomach ACE2 measurements, tissues were homogenized in the presence of a general protease inhibitor (PMSF) and specific ACE inhibitors.
- PMSF general protease inhibitor
- PGE 2 was obtained from Sigma, MPO activity kit from CytoStore and purified rACE and substrate from R&D Systems.
- V2 15% hydroxypropyl ⁇ -cyclodextrin (pH 5; final pH 11-12 with GLlOOl)
- V4 1% carboxymethylcellulose (pH 5; final pH ⁇ 8 with diclofenac)
- ACE2 activity was measured to determine the extent of inhibition of ACE2 in stomach tissues.
- the average activity of ACE2 in normal gastric tissue of naive animals was 772 pmoles/rag, as shown by the vehicle control group (Group A).
- ACE2 activity was significantly reduced to 436 pmoles/mg (Group C vs. Group B, p ⁇ 0.0001).
- the fluorescence signal in the ACE2 assay could come from ACE2 activity, which cleaves the last residue of the quenched fluorescent tripept ⁇ de substrate used in the assay, from background fluorescence or from cleavage of the tripept ⁇ de substrate by proteases other than ACE2. Consequently, in order to be able to ascribe ACE2 specific activity to the observed fluorescence signal, we determined the extent of GL 1001 -inhabitable signal in the tissue samples. Duplicate tissue samples corresponding to Groups A, B and C were either incubated ("spiked") with a vast excess of GLlOOl (>ICc ⁇ o) or not spiked.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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JP2010550811A JP2011513491A (en) | 2008-03-10 | 2009-03-10 | Treatment of proximal gastrointestinal disorders |
EP09720102A EP2262491A1 (en) | 2008-03-10 | 2009-03-10 | Therapy for disorders of the proximal digestive tract |
CA2717660A CA2717660A1 (en) | 2008-03-10 | 2009-03-10 | Therapy for disorders of the proximal digestive tract |
AU2009223644A AU2009223644A1 (en) | 2008-03-10 | 2009-03-10 | Therapy for disorders of the proximal digestive tract |
IL207977A IL207977A0 (en) | 2008-03-10 | 2010-09-05 | Therapy for disorders of the proximal digestive tract |
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US3527108P | 2008-03-10 | 2008-03-10 | |
US61/035,271 | 2008-03-10 |
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WO2009114516A1 true WO2009114516A1 (en) | 2009-09-17 |
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PCT/US2009/036642 WO2009114516A1 (en) | 2008-03-10 | 2009-03-10 | Therapy for disorders of the proximal digestive tract |
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US (1) | US20100035848A1 (en) |
EP (1) | EP2262491A1 (en) |
JP (1) | JP2011513491A (en) |
AU (1) | AU2009223644A1 (en) |
CA (1) | CA2717660A1 (en) |
IL (1) | IL207977A0 (en) |
WO (1) | WO2009114516A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011088075A2 (en) * | 2010-01-13 | 2011-07-21 | Ore Pharmaceuticals Inc. | Novel salts, polymorphs, and synthetic processes regarding imidazole derivative |
Families Citing this family (2)
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EP3430128A4 (en) | 2016-03-18 | 2020-05-13 | The Texas A&M University System | Using microbiota metabolites ot differentiate naive t-cells and related methods to induce or prevent inflammatory conditions |
WO2024117797A1 (en) * | 2022-11-29 | 2024-06-06 | 제일약품 주식회사 | Pharmaceutical composition for prevention or treatment of drug-related peptic ulcer comprising zastaprazan or pharmaceutically acceptable salt thereof |
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WO2002012471A2 (en) * | 2000-08-09 | 2002-02-14 | Millennium Pharmaceuticals, Inc. | Angiotensin converting enzyme homolog and uses therefor |
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US6900033B2 (en) * | 2001-06-04 | 2005-05-31 | Human Genome Sciences, Inc. | Methods and compositions for modulating ACE-2 activity |
WO2008031013A1 (en) * | 2006-09-08 | 2008-03-13 | Gene Logic Inc. | Method for treating inflammatory diseases of the digestive tract |
WO2008031014A1 (en) * | 2006-09-08 | 2008-03-13 | Ore Pharmaceuticals Inc. | Method for reducing or alleviating inflammation in the digestive tract |
WO2009049022A1 (en) * | 2007-10-10 | 2009-04-16 | Ore Pharmaceuticals Inc. | Method for treatment of pancreatitis |
-
2009
- 2009-03-10 WO PCT/US2009/036642 patent/WO2009114516A1/en active Application Filing
- 2009-03-10 CA CA2717660A patent/CA2717660A1/en not_active Abandoned
- 2009-03-10 AU AU2009223644A patent/AU2009223644A1/en not_active Abandoned
- 2009-03-10 EP EP09720102A patent/EP2262491A1/en not_active Withdrawn
- 2009-03-10 JP JP2010550811A patent/JP2011513491A/en active Pending
- 2009-03-10 US US12/401,143 patent/US20100035848A1/en not_active Abandoned
-
2010
- 2010-09-05 IL IL207977A patent/IL207977A0/en unknown
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US6632830B1 (en) * | 1999-04-30 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | ACE-2 inhibiting compounds and methods of use thereof |
WO2002012471A2 (en) * | 2000-08-09 | 2002-02-14 | Millennium Pharmaceuticals, Inc. | Angiotensin converting enzyme homolog and uses therefor |
US6900033B2 (en) * | 2001-06-04 | 2005-05-31 | Human Genome Sciences, Inc. | Methods and compositions for modulating ACE-2 activity |
WO2008031013A1 (en) * | 2006-09-08 | 2008-03-13 | Gene Logic Inc. | Method for treating inflammatory diseases of the digestive tract |
WO2008031014A1 (en) * | 2006-09-08 | 2008-03-13 | Ore Pharmaceuticals Inc. | Method for reducing or alleviating inflammation in the digestive tract |
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GUZMAN, L. (REPRINT); ODATE, S.; BOISELLE, C.; GROSS, S.; DONAHUE, S.: "GL1001 Inhibition of ACE2 is Gastroprotective in Rat Models of Gastritits", INFLAMMATORY BOWEL DISEASES, vol. 14, no. 12, December 2008 (2008-12-01), HOBOKEN, NJ 07030 USA, pages S14, XP008106726, ISSN: 1078-0998 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011088075A2 (en) * | 2010-01-13 | 2011-07-21 | Ore Pharmaceuticals Inc. | Novel salts, polymorphs, and synthetic processes regarding imidazole derivative |
WO2011088075A3 (en) * | 2010-01-13 | 2011-11-10 | Ore Pharmaceuticals Inc. | Novel salts, polymorphs, and synthetic processes regarding imidazole derivative |
Also Published As
Publication number | Publication date |
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EP2262491A1 (en) | 2010-12-22 |
IL207977A0 (en) | 2010-12-30 |
JP2011513491A (en) | 2011-04-28 |
AU2009223644A1 (en) | 2009-09-17 |
CA2717660A1 (en) | 2009-09-17 |
US20100035848A1 (en) | 2010-02-11 |
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