WO2023066893A1 - Dérivés d'amiloride pour le traitement d'une inflammation dans les intestins - Google Patents
Dérivés d'amiloride pour le traitement d'une inflammation dans les intestins Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to the field of methods for medical treatment of humans and animals, and compounds for use in such methods.
- the invention relates to treatment of conditions caused or complicated by inflammation in the intestines.
- Inflammation is part of the normal response of a host to microbial assault or injury.
- An acute inflammatory response is often initiated rapidly after recognition of a danger signal from the organ involved, and is coordinated by multiple chemokines, cytokines, eicosanoid neurotransmitters and other pro-inflammatory mediators produced by both resident immune cells and cells of the injured or infected tissue. This is often followed by a rapid influx of immunocytes, and self-amplifying networks of pro-inflammatory pathways perpetuate this signaling cascade until resolved.
- the inflammatory response is programmed to be contained in time and space and subsequently return to a baseline state corresponding to that preceding inflammation (Barnig et aL, 2019). These interactions are dysregulated in multiple inflammatory systemic disorders.
- a demonstration of this phenomenon is in inflammatory bowel diseases, where, epithelial barrier defects and dysregulated immune responses are central in ulcerative colitis (Barnig et aL, 2019) (Ungaro et aL, 2017) as well as Crohn’s disease (Barnig et aL, 2019).
- the intestinal epithelium comprises a single layer of epithelial cells and is a dynamic tissue containing protrusions and invaginations. Its functions include physical barrier properties, absorption of nutrients, and responding to signals both from the immune system and the microbiota (Chang et aL, 2020). Perturbation of this complex interplay, involving aberrant intestinal turnover and inflammatory cytokines such as interleukin 1 and TNF alpha (Xia et aL, 1998) is a feature of inflammatory bowel disease, and can lead to ulceration, bleeding, toxic megacolon, fulminant colitis, strictures, fistulas, or abscesses (Chang et aL, 2020).
- Amiloride (3,5-diamino-6-chloro-A/-(diaminomethylidene)pyrazine-2-carboxamide) is used, in the hydrochloride salt form, to inhibit sodium reabsorption through sodium channels in renal epithelial cells. This inhibition creates a negative potential in the luminal membranes of principal cells, located in the distal convoluted tubule and collecting duct. Negative potential reduces secretion of potassium and hydrogen ions. Amiloride is used in conjunction with diuretics to spare potassium loss. Amiloride has been suggested to suppress disease activity in a mouse model of Inflammatory Bowel Disease (Nemeth et al., 2002).
- the present invention relates to a method of treating a medical condition involving an inflammation in the intestines in a subject by administering to a subject in need thereof an effective dose of a compound represented by formula (I) wherein R is selected from
- the inflammation is an inflammation in the intestinal epithelium.
- the inflammation is an inflammation of the duodenum, jejunum, ileum, cecum, colon and/or rectum.
- the medical condition is selected from the group consisting of ulcerative colitis, Crohn’s Disease, Microscopic Colitis, Pseudomembranous Colitis, Inflammatory Bowel Syndrome, and celiac disease.
- the compound is administered per oral, intravenous, intramuscular, transcutaneous, subcutaneous or per rectum.
- the compound is administered in a pharmaceutical composition adapted for controlled release of the compound in the intestine.
- the pharmaceutically acceptable salt is the lactic, acetic, or phosphoric acid salt.
- the compound is benzamil.
- the present invention relates to the compounds as defined above, or a pharmaceutically acceptable salt thereof, for use in a method according to the invention.
- the present invention relates to the use of the compounds as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for use in a method according to any one of the preceding claims.
- Figure 1 it is shown that benzamil, but not amiloride, Camostat Mesilate (extracellular ENaC inhibitor with different off-target profile), KB-R7943 (NCX1 inhibitor) or Zoniporide (NHE inhibitor), significantly normalizes cytokine induced colonic cell hyperproliferation under stimulation by IL17 and TNFa (10 ng/ml for 48 hours)
- NHE The Na + -H + exchanger (NHE) is the major mechanism whereby heart cells regulate intracellular pH. There are at least six NHE isoforms thus far identified, with the NHE1-NHE5 apparently restricted to the plasma membrane, whereas NHE6 might be a mitochondrial isoform. NHE is composed of two major domains, a transmembrane domain and a large intracellular cytoplasmic domain (Wang et al., 2012).
- ENaC The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na + ions across high resistance epithelia, maintaining body salt and water homeostasis (Hanukoglu et al., 2016).
- ASIC Acid-sensing ion channels
- ASICs are Na + channels activated by external protons.
- the ASIC channels constitute a subfamily within the larger ENaC superfamily.
- ASICs share about 20-25% identity with the ENaC channels but display all the characteristics of the superfamily, which are, two transmembrane spanning domains, a large extracellular domain and short intracellular N and C termini.
- NCX The sodium-calcium exchanger (also denoted Na + /Ca 2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells.
- the present inventors have surprisingly found that benzamil significantly reduces cytokine-induced hyper-proliferation in colon epithelial cells, while this is not the case for the closely related compound amiloride or for specific ENAC, NHE or NCX inhibitors.
- the present inventors have also found that benzamil reduces production of pro- inflammatory cytokines TNFa and IL-1 a in colon epithelial cells.
- the present invention thus describes the use of specific amiloride derivatives that has a combined off target profile that has a directionality that mimics benzamil, with activity on all three ion channels ENaC, NHE1 and NCX1.
- amiloride derivatives are distinct and differential in their effect on intestinal inflammation compared to specific ENaC inhibitors with reduced or no activity on NHE and NCX.
- the present invention utilizes combined inhibition of multiple ion channels (ENaC, NHE and NCX) by amiloride-derived drugs to reduce production of cytokines involved in intestinal inflammation, where expression or activity of several of these channels is dysregulated, enabling these drugs as treatment of conditions caused or complicated by inflammation in the intestines.
- EaC multiple ion channels
- NCX NCX
- Amiloride derivatives useful in the present invention are those of formula (I)
- a method of treating a medical condition involving an inflammation in the intestines in a subject by administering to a subject in need thereof an effective dose of a compound represented by formula (I), as described above.
- the inflammation is an inflammation in the intestinal epithelium, such as an inflammation of the duodenum, jejunum, ileum, cecum, colon and/or rectum.
- the medical condition is selected from the group consisting of ulcerative colitis, Crohn’s Disease, Microscopic Colitis, Pseudomembranous Colitis, Inflammatory Bowel Syndrome, and celiac disease.
- the present invention makes use of a pharmaceutically acceptable salt of the compounds of the invention.
- a pharmaceutically acceptable salt of the compounds of the invention in particular the lactic acid, acetic acid, and phosphoric acid salts of benzamil have improved properties as compared to the free base compound and other salts in terms of stability, water solubility, hygroscopicity, and polymorphism.
- the pharmaceutically acceptable salt is the lactic, acetic, or phosphoric acid salt.
- a composition comprising an effective dose of the compounds of the invention, optionally combined with additional therapeutic agents, may be provided to an individual suffering from an inflammation in the intestines.
- the administration can preferably be per oral or per rectum.
- the dosing and periodicity of administration is selected to provide for therapeutic efficacy.
- the present invention thus relates to and makes use of pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of at least one compound of the invention, optionally combined with one or more additional agents for treatment of an inflammation in the intestines, formulated together with one or more pharmaceutically acceptable excipients.
- the active ingredients and excipient(s) may be formulated into compositions and dosage forms according to methods known in the art.
- compositions of the present invention may be formulated for administration in solid, liquid or semi-liquid form, including those adapted for the following: oral administration, for example, tablets, suppositories, capsules, powders, granules, pastes for application to the tongue, aqueous or non-aqueous solutions or suspensions, drenches, or syrups.
- oral administration for example, tablets, suppositories, capsules, powders, granules, pastes for application to the tongue, aqueous or non-aqueous solutions or suspensions, drenches, or syrups.
- the medicaments, pharmaceutical compositions or therapeutic combinations according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
- the pharmaceutical composition is adapted for controlled release of the compound in the intestine, such as for controlled release in the duodenum, jejunum, ileum, cecum, colon or rectum.
- the medicament, (pharmaceutical) composition or therapeutic combination can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of “Pharmaceutics: The Science of Dosage Forms”, Second Edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology”, Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); “Modern Pharmaceutics”, Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New York 2002 y “The Theory and Practice of Industrial Pharmacy”, Lachman L., Lieberman H. And Kanig J.
- An effective dose of the compounds of the invention may include a "therapeutically effective dose or amount” or a “prophylactically effective dose or amount”.
- a “therapeutically effective dose/amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
- a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability to elicit a desired response in the individual.
- a therapeutically effective dose/amount is also one in which any toxic or detrimental effects are outweighed by the therapeutically beneficial effects.
- prophylactically effective dose/amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
- Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. The dose may be administered to the subject upon symptoms of an inflammation in the intestines, or before onset of symptoms.
- a therapeutic or prophylactic response e.g., a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
- the dose may be administered to the subject upon symptoms of an inflammation in the intestines, or before onset of symptoms.
- dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the term "dose amount” refers to the quantity, e.g., milligrams (mg), of the substance which is administered to the subject.
- the dose amount is a fixed dose, e.g., is not dependent on the weight of the subject to which the substance is administered.
- the dose amount is not a fixed dose, e.g., is dependent on the weight of the subject to which the substance is administered.
- Exemplary dose amounts for use in treating an adult human may include, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 500 mg, or more.
- Ranges intermediate to the above-recited ranges are also contemplated.
- ranges having any one of these values as the upper or lower limits are also intended to be part of the invention, e.g., about 0.01 mg to about 100 mg, about 1 mg to about 10 mg, etc.
- the administration of the composition may comprise a recurring cycle of administration of composition to the subject.
- the periodicity of administration of the compound may be about once a week, once every other week, about once every three weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 1 1 weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, about once every 16 weeks, about once every 17 weeks, about once every 18 weeks, about once every 19 weeks, about once every 20 weeks, about once every 21 weeks, about once every 22 weeks, about once every 23 weeks, about once every 24 weeks, about once every 5-10 days, about once every 10-20 days, about once every 10-50 days, about once every 10- 100 days, about once every 10-200 days, about once every 25-35 days, about once every 20-50 days, about once every 20-100 days, about once every 20-200 days, about once every 30-50 days, about once every 30-90 days, about once every 30-100 days, about once every 30-200 days, about once every 50-150
- Periodicities intermediate to the above-recited times are also contemplated by the invention. Ranges intermediate to the above-recited ranges are also contemplated by the invention. For example, ranges having any one of these values as the upper or lower limits are also intended to be part of the invention, e.g., about 1 10 days to about 170 days, about 160 days to about 220 days, etc.
- “Duration of a periodicity” refers to a time over which the recurring cycle of administration occurs.
- a duration of the periodicity of administration of a substance may be may be up to about 4 weeks, up to about 8 weeks, up to about 12 weeks, up to about 16 weeks or more, up to about 20 weeks, up to about 24 weeks, up to about 28 week, up to about 32 weeks or more, during which the periodicity of administration is about once every week.
- a duration of the periodicity may be about 6 weeks during which the periodicity of administration is about once every 4 weeks, e.g., the substance is administered at week zero and at week four.
- Example 1 Colon Epithelial Cell Inflammation Assay
- GM Growth media
- BM basal media
- PBS phosphate buffered saline
- IL-17A stock solutions of 100 pg/mL were prepared in PBS and aliquoted to be stored at -20°C for the duration of the study.
- IL-17A was diluted with BM and added to each well for a final concentration of 10 ng/mL.
- BM Basal medium
- Camostat mesilate is an extracellular ENaC inhibitor
- KB-R7943 is an NCX1 inhibitor
- zoniporide is an NHE inhibitor.
- DMSO (Sigma) was used as vehicle, and TNFa (R&D Systems ) and IL-17A (R&D Systems) as stimulants.
- test compounds 100 pL of above prepared test compounds were added to appropriate wells to reach a final volume per well of 200 pL. Samples were incubated for 48 hours.
- cytokine analysis The inflammatory cytokines, including CXCL2, IL-1 a, TNFa, CXCL1 , TGFa, TGF0, CCL2, IL-6, IL-8, CCL20 in the cell culture supernatants were analyzed by Luminex.
- Epithelial sodium channel (ENaC) family Phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene, 579(2), 95-132.
- Na+/H+ exchanger blockade inhibits enterocyte inflammatory response and protects against colitis. Am J Physiol Gastrointest Liver Physiol, 283, G122-G132.
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Abstract
La présente invention concerne une méthode de traitement d'un état médical impliquant une inflammation dans les intestins chez un sujet, par l'administration à un sujet dont l'état le nécessite, d'une dose efficace d'un composé représenté par la formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci.
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