WO2023237542A1 - O-glcnacase inhibition as a treatment for acute decompensated heart failure - Google Patents

O-glcnacase inhibition as a treatment for acute decompensated heart failure Download PDF

Info

Publication number
WO2023237542A1
WO2023237542A1 PCT/EP2023/065100 EP2023065100W WO2023237542A1 WO 2023237542 A1 WO2023237542 A1 WO 2023237542A1 EP 2023065100 W EP2023065100 W EP 2023065100W WO 2023237542 A1 WO2023237542 A1 WO 2023237542A1
Authority
WO
WIPO (PCT)
Prior art keywords
heart failure
oga
inhibitor
treatment
glcnacase
Prior art date
Application number
PCT/EP2023/065100
Other languages
French (fr)
Inventor
Florence Pinet
Paul Mulder
Original Assignee
Institut National de la Santé et de la Recherche Médicale
Centre Hospitalier Universitaire De Lille
Université De Rouen Normandie
Institut Pasteur De Lille
Université de Lille
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire De Lille, Université De Rouen Normandie, Institut Pasteur De Lille, Université de Lille filed Critical Institut National de la Santé et de la Recherche Médicale
Publication of WO2023237542A1 publication Critical patent/WO2023237542A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention is in the field of medicine, in particular cardiology.
  • HF acute decompensated heart failure
  • ADHF Alzheimer's disease
  • the present invention is defined by the claims.
  • the present invention relates to the use of O-GlcNAcase inhibitors for the treatment of acute decompensated heart failure.
  • the first object of the present invention relates to a method of treating acute decompensated heart failure in patient in need thereof comprising administering to the patient a therapeutically effective amount of a O-GlcNAcase inhibitor.
  • ADHF acute decompensated heart failure
  • HF heart failure
  • pulmonary and systemic congestion due to increased left- and right-heart filling pressures is a nearly universal finding in ADHF.
  • the onset and severity of symptoms of ADHF vary and depend importantly on the nature of the underlying cardiac disease and the rate at which the syndrome develops.
  • the largest proportion of patients (70%) with ADHF are admitted due to worsening chronic HF, up to 15 to 20% of patients present with HF for the first time, and approximately 5% are admitted for advanced or end-stage HF.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the OGA inhibitor is particularly suitable for improving left ventricular function, and more particularly for improving cardiac output and myocardial tissue perfusion.
  • O-GlcNAcase or “OGA” has its general meaning in the art and refers to an enzyme with systematic name (protein)-3-O-(N-acetyl-D-glucosaminyl)-L- serine/threonine N-acetylglucosaminyl hydrolase (EC 3.2.1.169).
  • the term is also known as glycoside hydrolase O-GlcNAcase, BtGH84, or O-GlcNAc hydrolase.
  • the enzyme is encoded by the MGEA5 gene (Gene ID: 10724).
  • This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction: [protein]-3-O-(N-acetyl-P- D-glucosaminyl)-L-serine + H2O [protein] -L-serine + N-acetyl-D-glucosamine.
  • O-GlcNAcase inhibitor or “OGA inhibitor” refers to any compound natural or not which is capable of inhibiting the activity of OGA.
  • the term encompasses any OGA inhibitor that is currently known in the art or that will be identified in the future.
  • the term also encompasses inhibitor of expression.
  • Assays for determining whether a compound is an OGA inhibitor are well known in the art (e.g. AlteenMG, Tan HY, Vocadlo DJ Monitoring and modulating O-GlcNAcylation: assays and inhibitors of O-GlcNAc processing enzymes. Curr Opin Struct Biol. 2021 Jun;68: 157-165. doi: 10.1016/j.sbi.2020.12.008. Epub 2021 Jan 31. PMID: 33535148.).
  • OGA inhibitors are well known in the art and include those described in:
  • O-GlcNAcase inhibitor has protective effects in intracerebral hemorrhage by suppressing the inflammatory response. Neuroreport. 2021 Dec 8; 32(17): 1349-1356. doi: 10.1097/WNR.0000000000001734. PMID: 34718246.
  • the OGA inhibitor of the present invention is selected among Thiazoline derivatives, GlcNAcstatins and related glucoimidazoles, Imminocyclitols, Thioglycoside- naphthalimide hybrids, 1,2,3-Triazole-based derivatives, a-GlcNAc thiosulfonate and Noncarbohydrate-based inhibitors.
  • the OGA inhibitor of the present invention is selected from the group consisting of PUGNAc (O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N- phenylcarbamate), 2’-Methyl-a-d-glucopyrano-[2,l-d]-52’-thiazoline (NAG-thiazoline, NG), NButGt, Thiamet-G ((3aR,5R,6S,7R,7aR)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5- (hydroxymethyl)-5H-Pyrano[3,2-d]thiazole-6,7-diol), 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas), MK-8719 from Merck/ Alectos, ASN-120,290 from Asceneuron S.A. and LY- 3,372,689 from Eli Lilly
  • the OGA inhibitor has the formula of:
  • the OGA inhibitor is an inhibitor of OGA expression.
  • An “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.
  • anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of OGA mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of OGA, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding OGA can be synthesized, e.g., by conventional phosphodiester techniques.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
  • Small inhibitory RNAs siRNAs
  • siRNAs can also function as inhibitors of expression for use in the present invention.
  • OGA gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that OGA gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference or RNAi
  • Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing OGA.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus/lentivirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • adenovirus adeno-associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses Epstein-Barr viruses
  • papilloma viruses herpes virus
  • the term "therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount of the active agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of drug are outweighed by the therapeutically beneficial effects.
  • the efficient dosages and dosage regimens for the active agent depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable dose of a composition of the present invention will be that amount of the compound, which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen.
  • Such an effective dose will generally depend upon the factors described above.
  • a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the patient's size, the severity of the patient's symptoms, and the particular composition or route of administration selected.
  • An exemplary, non-limiting range for a therapeutically effective amount of a drug of the present invention is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg.
  • An exemplary, non-limiting range for a therapeutically effective amount of a drug of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg.
  • the OGA inhibitor of the present invention is administered to the patient in one single administration.
  • single administration refers to an administration of a drug that is provided as a one dose given once, at a certain time point.
  • the active ingredient of the present invention e.g. OGA inhibitor
  • pharmaceutically acceptable excipients e.g. OGA inhibitor
  • sustained-release matrices such as biodegradable polymers
  • composition refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients.
  • the pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier.
  • the term “pharmaceutically acceptable carrier” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • the pharmaceutically acceptable carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 2 Myocardial tissue perfusion.
  • FIG. 1 Coronary relaxation.
  • Figure 4. Effect of Thiamet G on cardiac output. Arrows indicate NaCl loading. Thiamet G is administered 12h after NaCl loading.
  • ADHF -induced further aggravation of left ventricular dysfunction is associated with immediate and persistent reduction of myocardial tissue perfusion (Fig. 2) and with a 12h delay an impairment of coronary dysfunction (Fig. 3), which is probably involved or responsible for incomplete recovery of ADHF.
  • Fig. 2 myocardial tissue perfusion
  • Fig. 3 coronary dysfunction
  • S38844 [6] when completely restores immediately left ventricular function, i.e. cardiac output, and myocardial perfusion (Fig. 2) as well as coronary relaxation (Fig. 3).
  • delayed transient heart rate reduction initiated 6 days after decompensation, in a context of cardiac dysfunction, and reduced myocardial perfusion as well as impaired coronary function, not improves the pathophysiological state of decompensation [6]
  • This difference in efficacy between early and delayed heart rate reduction likely reflects the divergent temporal evolution of the multiples mechanisms implicated in either the early or the delayed/recovery phase resulting from the creation of a vicious circle initiated during the acute phase.
  • the reduced left ventricular perfusion in response to salt-loading, will immediately decrease myocardial O2 supply resulting in immediate aggravation of cardiac dysfunction.

Abstract

Exacerbation of heart failure, better known as acute decompensated heart failure (HF), is characterized by dyspnea, edema and fatigue, and is a growing medical problem. The inventors demonstrated that transient O-GlcNAcase inhibition would be suitable for the treatment of acute decompensated heart failure. In particular they used two recently developed models mimicking acute decompensation of heart failure patients, and deciphered mechanisms susceptible to be involved in this cardiovascular protection, with a focus on post-translational cardiac protein modifications and metabolic remodeling. Accordingly, the present invention relates to the use of O-GlcNAcase inhibitors for the treatment of acute decompensated heart failure.

Description

O-GLCNACASE INHIBITION AS A TREATMENT FOR ACUTE DECOMPENSATED HEART FAILURE
FIELD OF THE INVENTION:
The present invention is in the field of medicine, in particular cardiology.
BACKGROUND OF THE INVENTION:
Exacerbation of heart failure, better known as acute decompensated heart failure (HF), is characterized by dyspnea, edema and fatigue, and is a growing medical problem [1], Indeed, acute decompensated heart failure, representing 1 to 2% of all hospitalization in Europe, is today the leading cause of hospitalization for people older than 65 years [2] and is associated, despite current medical treatments, with a high morbidity and mortality, as illustrated by the 8- 20% mortality following the 2 months after hospital admission for ADHF [2, 3], Moreover, acute decompensation renders prone for recurrent decompensation [4] and re-hospitalization, illustrated by the cardiovascular death and re-hospitalization rates for acute heart failure (27 and 37 % at 6 and 12 months, respectively), as observed by the ASTRONAUT trial [5],
It must be pointed out that upon patient hospitalization, neither the time-span between the trigger and hospitalization nor the nature of the ‘trigger’ among the large variety of causes known to provoke acute decompensation (such as excessive salt intake and atrial fibrillation), are often unknown. This renders treatment stratification extremely difficult, and it is likely that incoherent patient stratification upon hospital admission contributes to the relative inefficacy of treatments, but also is involved in the incomplete recovery of cardiac function over time observed in ADHF. Moreover, relative inefficacy of treatments is also hindered the limited knowledge of the complex interplay of the multitude of organs (left ventricle, lungs, kidney and brain) and of the multiple mechanisms (oxidative stress, inflammation and post-translational protein modifications) during the evolution of ADHF.
Thus, a better comprehension of the acute, semi-acute, and chronic mechanisms as well as the different organs involved in acute decompensation will improve patient/treatment stratification via enhanced early and mid-term cardiac recovery, and thus reduce re-admission for ‘secondary’ decompensation and finally improve patient outcome. Although agents for the management of chronic HF continue to expand and the arsenal of guideline-directed medical therapies is robust, the same cannot be said for management of ADHF (Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, et aL. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a Report of the American College of Car diology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.Circulation. 2017; 136:e 137 e 161). Despite scores of years of research and development, the main pharmacological therapies for ADHF indeed remain diuretics, vasodilators, and calcitropes (inotropes that improve cardiac function by altering myocardial calcium transients). ADHF is a distinct entity from chronic heart failure (CHF) with a multifaceted pathophysiology that has yet to be clearly elucidated and, therefore, not effectively managed.
An interplay between troponin T phosphorylation and O-N-acetylglucosaminylation in ischaemic heart failure have been already disclosed (Dubois-Deruy E, Belliard A, Mulder P, Bouvet M, Smet-Nocca C, Janel S, Lafont F, Beseme O, Amouyel P, Richard V, Pinet F. Interplay between troponin T phosphorylation and O-N-acetylglucosaminylation in ischaemic heart failure. Cardiovasc Res. 2015 Jul l;107(l):56-65. doi: 10.1093/cvr/cvvl36. Epub 2015 Apr 26. PMID: 25916824) and suggests that chronic administration of -GlcNAcase inhibitors would be of interest for the treatment of chronic heart failure but the interest in ADHF has not yet been investigated.
SUMMARY OF THE INVENTION:
The present invention is defined by the claims. In particular, the present invention relates to the use of O-GlcNAcase inhibitors for the treatment of acute decompensated heart failure.
DETAILED DESCRIPTION OF THE INVENTION:
The inventors demonstrated that transient O-GlcNAcase inhibition would be suitable for the treatment of acute decompensated heart failure. In particular they used two recently developed models mimicking acute decompensation of heart failure patients, and deciphered mechanisms susceptible to be involved in this cardiovascular protection, with a focus on post-translational cardiac protein modifications and metabolic remodeling. Accordingly, the first object of the present invention relates to a method of treating acute decompensated heart failure in patient in need thereof comprising administering to the patient a therapeutically effective amount of a O-GlcNAcase inhibitor.
As used herein, the term “acute decompensated heart failure” or “ADHF” has its general meaning in the art and refers to the sudden or gradual onset of the signs or symptoms of heart failure (HF) requiring unplanned office visits, emergency room visits, or hospitalization. Regardless of the underlying precipitant of the exacerbation, pulmonary and systemic congestion due to increased left- and right-heart filling pressures is a nearly universal finding in ADHF. The onset and severity of symptoms of ADHF vary and depend importantly on the nature of the underlying cardiac disease and the rate at which the syndrome develops. The largest proportion of patients (70%) with ADHF are admitted due to worsening chronic HF, up to 15 to 20% of patients present with HF for the first time, and approximately 5% are admitted for advanced or end-stage HF.
As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
In particular, the OGA inhibitor is particularly suitable for improving left ventricular function, and more particularly for improving cardiac output and myocardial tissue perfusion.
As used herein, the term “O-GlcNAcase” or “OGA” has its general meaning in the art and refers to an enzyme with systematic name (protein)-3-O-(N-acetyl-D-glucosaminyl)-L- serine/threonine N-acetylglucosaminyl hydrolase (EC 3.2.1.169). The term is also known as glycoside hydrolase O-GlcNAcase, BtGH84, or O-GlcNAc hydrolase. The enzyme is encoded by the MGEA5 gene (Gene ID: 10724). This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction: [protein]-3-O-(N-acetyl-P- D-glucosaminyl)-L-serine + H2O [protein] -L-serine + N-acetyl-D-glucosamine.
As used herein, the term “O-GlcNAcase inhibitor” or “OGA inhibitor” refers to any compound natural or not which is capable of inhibiting the activity of OGA. The term encompasses any OGA inhibitor that is currently known in the art or that will be identified in the future. The term also encompasses inhibitor of expression. Assays for determining whether a compound is an OGA inhibitor are well known in the art (e.g. AlteenMG, Tan HY, Vocadlo DJ Monitoring and modulating O-GlcNAcylation: assays and inhibitors of O-GlcNAc processing enzymes. Curr Opin Struct Biol. 2021 Jun;68: 157-165. doi: 10.1016/j.sbi.2020.12.008. Epub 2021 Jan 31. PMID: 33535148.). OGA inhibitors are well known in the art and include those described in:
Bartolome-Nebreda JM, Trabanco AA, Velter Al, Buijnsters P. O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer's disease and related tauopathies: analysis of the patent literature. Expert Opin Ther Pat. 2021 Dec;31(12):1117-1154. doi: 10.1080/13543776.2021.1947242. Epub 2021 Jul 8. PMID: 34176417).
Gonzdlez-Cuesta M, Sidhu P, Ashmus RA, Males A, Proceviat C, Madden Z, Rogalski JC, Busmann JA, Foster LJ, Garcia Fernandez JM, Davies GJ, Ortiz Mellet C, Vocadlo DJ. Bicyclic Picomolar OGA Inhibitors Enable Chemoproteomic Mapping of Its Endogenous Post-translational Modifications. J Am Chem Soc. 2022 Jan 19; 144(2) :832-844. doi: 10.1021/jacs.lcl0504. Epub 2022 Jan 5. PMID: 34985906. He Y, Liu H, Liu Y, Li X, Fan M, Shi K, Li M. O-GlcNAcase inhibitor has protective effects in intracerebral hemorrhage by suppressing the inflammatory response. Neuroreport. 2021 Dec 8; 32(17): 1349-1356. doi: 10.1097/WNR.0000000000001734. PMID: 34718246.
Sabnis RW. Benzo [d]thiazol-5-yl Compounds as O-GlcNAcase Inhibitors for Treating Alzheimer's Disease. ACS Med Chem Lett. 2021 May 18;12(6):947-948. doi: 10.1021/acsmedchemlett.lc00259. PMID: 34141076; PMCID: PMC8201512.
Pan D, Gu JH, Zhang J, Hu Y, Liu F, Iqbal K, Cekic N, Vocadlo DJ, Dai CL, Gong CX. Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice. J Alzheimer s Dis. 2021;81(l):273-286. doi: 10.3233/JAD-201450. PMID: 33814439.
Tawada M, Fushimi M, Masuda K, Sun H, Uchiyama N, Kosugi Y, Lane W, Tjhen R, Endo S, Koike T. Discovery of a Novel and Brain-Penetrant O-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization. J Med Chem. 2021 Jan 28;64(2): 1103-1115. doi: 10.1021/acs.jmedchem.0c01712. Epub 2021 Jan 6. PMID: 33404239.
- Martinez-Viturro CM, Trabanco AA, RoyesJ, Fernandez E, Tresadern G, Vega J A, Del Cerro A, Delgado F, Garcia Molina A, Tovar F, Shaffer P, Ebneth A, Bretteville A, Mertens L, Somers M, Alonso JM, Bartolome-Nebreda JM. Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders. J Med Chem. 2020 Nov 25 ;63(22): 14017-14044. doi: 10.1021/acs.jmedchem.0c01479. Epub 2020 Nov 16. PMID: 33197187.
Elbatrawy AA, Kim EJ, Nam G. O-GlcNAcase: Emerging Mechanism, Substrate Recognition and Small-Molecule Inhibitors. ChemMedChem. 2020 Jul 20; 15(14): 1244- 1257. doi: 10.1002/cmdc.202000077. Epub 2020 Jun 16. PMID: 32496638.
Wang X, Li W, Marcus J, Pearson M, Song L, Smith K, Terracina G, Lee J, Hong KK, Lu SX, Hyde L, Chen SC, Kinsley D, Melchor JP, Rubins DJ, Meng X, Hostetler E, Sur C, Zhang L, Schachter JB, Hess JF, Seinick HG, Vocadlo DJ, McEachern EJ, Uslaner JM, Duffy JL, Smith SM. MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy. J Pharmacol Exp Ther. 2020 Aug; 374(2): 252-263. doi: 10.1124/jpet.120.266122. Epub 2020 Jun 3. PMID: 32493725.
Dong L, Shen S, Chen W, Xu D, Yang Q, Lu H, Zhang J. Discovery of Novel Inhibitors Targeting Human O-GlcNAcase: Docking-Based Virtual Screening, Biological Evaluation, Structural Modification, and Molecular Dynamics Simulation. J Chem Inf Model. 2019 Oct 28;59(10):4374-4382. doi: 10.1021/acs.jcim.9b00479. Epub 2019 Sep 17. PMID: 31487462.
Seinick HG, Hess JF, Tang C, Liu K, Schachter JB, Ballard JE, Marcus J, Klein DJ, Wang X, Pearson M, Savage MJ, Kaul R, Li TS, Vocadlo DJ, Zhou Y, Zhu Y, Mu C, Wang Y, Wei Z, Bai C, Duffy JL, McEachern EJ. Discovery ofMK-8719, a Potent O- GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. J Med Chem. 2019 Nov 27;62(22): 10062-10097. doi: 10.1021/acs.jmedchem.9b01090. Epub 2019 Sep 29. PMID: 31487175.
Shen S, Dong L, Chen W, Wu R, Lu H, Yang Q, Zhang J. Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase. Front Chem. 2019 Jul 25; 7:533. doi: 10.3389/fchem.2019.00533. PMID: 31403045; PMCID: PMC6669961.
Shen S, Dong L, Chen W, Zeng X, Lu H, Yang Q, Zhang J. Modification of the Thioglycosyl-Naphthalimides as Potent and Selective Human O-GlcNAcase Inhibitors. ACS Med Chem Lett. 2018 Nov 15;9(12): 1241-1246. doi: 10.1021/acsmedchemlett.8b00406. PMID: 30613333; PMCID: PMC6295843.
Igual MO, Nunes PSG, da Costa RM, Mantoani SP, Tostes RC, Carvalho I. Novel glucopyranoside C2-derived 1,2, 3 -triazoles displaying selective inhibition of O- GlcNAcase (OGA). Carbohydr Res. 2019 Jan l;471:43-55. doi: 10.1016/j. carres.2018.10.007. Epub 2018 Oct 26. PMID: 30412832.
Shen S, Chen W, Dong L, Yang Q, Lu H, Zhang J. Design and synthesis of naphthalimide group-bearing thioglycosides as novel f-N-acetylhexosaminidases inhibitors. J Enzyme Inhib Med Chem. 2018 Dec;33(l):445-452. doi: 10.1080/14756366.2017.1419217. PMID: 29390898; PMCID: PMC6009855.
In some embodiments, the OGA inhibitor of the present invention is selected among Thiazoline derivatives, GlcNAcstatins and related glucoimidazoles, Imminocyclitols, Thioglycoside- naphthalimide hybrids, 1,2,3-Triazole-based derivatives, a-GlcNAc thiosulfonate and Noncarbohydrate-based inhibitors. In some embodiments, the OGA inhibitor of the present invention is selected from the group consisting of PUGNAc (O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N- phenylcarbamate), 2’-Methyl-a-d-glucopyrano-[2,l-d]-52’-thiazoline (NAG-thiazoline, NG), NButGt, Thiamet-G ((3aR,5R,6S,7R,7aR)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5- (hydroxymethyl)-5H-Pyrano[3,2-d]thiazole-6,7-diol), 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas), MK-8719 from Merck/ Alectos, ASN-120,290 from Asceneuron S.A. and LY- 3,372,689 from Eli Lilly.
In some embodiments, the OGA inhibitor has the formula of:
Figure imgf000008_0001
16 MK-8719 17 GIcNAcstatin G 18 W-347
Kj = 7.9 nM Kj = 4.1 nM Ki = 8 nM
In some embodiments, the OGA inhibitor is an inhibitor of OGA expression. An “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene. In a preferred embodiment of the invention, said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme. For example, anti-sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of OGA mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of OGA, and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding OGA can be synthesized, e.g., by conventional phosphodiester techniques. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732). Small inhibitory RNAs (siRNAs) can also function as inhibitors of expression for use in the present invention. OGA gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that OGA gene expression is specifically inhibited (i.e. RNA interference or RNAi). Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing OGA. Typically, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus/lentivirus. One can readily employ other vectors not named but known to the art.
As used herein, the term "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount of the active agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of drug are outweighed by the therapeutically beneficial effects. The efficient dosages and dosage regimens for the active agent depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of active agent employed in the pharmaceutical composition at levels lower than that required achieving the desired therapeutic effect and gradually increasing the dosage until the desired effect is achieved. In general, a suitable dose of a composition of the present invention will be that amount of the compound, which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above. For example, a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease. One of ordinary skill in the art would be able to determine such amounts based on such factors as the patient's size, the severity of the patient's symptoms, and the particular composition or route of administration selected. An exemplary, non-limiting range for a therapeutically effective amount of a drug of the present invention is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg. An exemplary, non-limiting range for a therapeutically effective amount of a drug of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg.
In some embodiments, the OGA inhibitor of the present invention is administered to the patient in one single administration. The term “single administration” as used herein refers to an administration of a drug that is provided as a one dose given once, at a certain time point.
Typically the active ingredient of the present invention (e.g. OGA inhibitor) is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
As used herein, the term “pharmaceutical composition” refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients. The pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier.
As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. In particular, the pharmaceutically acceptable carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. In the pharmaceutical compositions of the present invention, the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.
FIGURES:
Figure 1. Evolution of cardiac output determined in repeated decompensated HF Arrow indicates salt - loading.
Figure 2. Myocardial tissue perfusion.
Figure 3. Coronary relaxation. Figure 4. Effect of Thiamet G on cardiac output. Arrows indicate NaCl loading. Thiamet G is administered 12h after NaCl loading.
EXAMPLE:
Recently, we developed an unique rodent model mimicking acute decompensation of heart failure after excessive dietary salt ingestion as observed in non-compliance with diet in patients [6], In this model acute decompensation is induced by salt-loading in rats with established chronic heart failure. As soon as 12 hours after of salt-loading, left ventricular function is impaired, as illustrated by the further decrease of the already by heart failure reduced cardiac output (Fig. 1). Moreover, after 3 repeated salt-loadings, cardiac recovery becomes progressively impaired, with absence of recovery for up to 4 weeks after the 3rd salt-loading. This is highly clinically relevant, as progressive worsening of cardiac function with impaired recovery after each acute episode is an important feature in acute decompensated heart failure patients.
It must be pointed out that ADHF -induced further aggravation of left ventricular dysfunction is associated with immediate and persistent reduction of myocardial tissue perfusion (Fig. 2) and with a 12h delay an impairment of coronary dysfunction (Fig. 3), which is probably involved or responsible for incomplete recovery of ADHF. We also demonstrated that early transient heart rate reduction, induced by transient short-term administration initiated 12 hours after decompensation (in a context of reduced cardiac function and myocardial perfusion, but preserved coronary vascular function), with the If current inhibitor S38844 [6], when completely restores immediately left ventricular function, i.e. cardiac output, and myocardial perfusion (Fig. 2) as well as coronary relaxation (Fig. 3). In contrast, delayed transient heart rate reduction, initiated 6 days after decompensation, in a context of cardiac dysfunction, and reduced myocardial perfusion as well as impaired coronary function, not improves the pathophysiological state of decompensation [6], This difference in efficacy between early and delayed heart rate reduction likely reflects the divergent temporal evolution of the multiples mechanisms implicated in either the early or the delayed/recovery phase resulting from the creation of a vicious circle initiated during the acute phase. Indeed, the reduced left ventricular perfusion, in response to salt-loading, will immediately decrease myocardial O2 supply resulting in immediate aggravation of cardiac dysfunction. Subsequently, if this reduction of left ventricular perfusion persists over time, it is likely to trigger myocardial tissue hypoxia/ischemia, an inflammatory response and oxidative stress, which by decreasing coronary NO bioavailability, will result in aggravated coronary endothelial dysfunction, persistent reduction in myocardial tissue perfusion, resulting in the incomplete recovery of cardiac function after acute phase of ADHF. However it must be pointed out that other cellular mechanisms, probably triggered by sustained hypoxia/ischemia during the acute phase of ADHF, succeed the initial mechanisms, which is suggested by the fact that delayed transient heart rate reduction does not oppose ADHF -related aggravation of cardiac and vascular dysfunction.
Among these mechanisms, post-translational modifications of cardiac proteins are probably involved. Indeed, data aiming the search for new biomarkers in heart failure and more specifically post-translational protein modifications [7-13], shows that as early as five hours after one single administration of Thiamet G left ventricular function is improved. This extreme rapid beneficial effect clearly suggests that increasing cardiac protein O-GlcNaCylation [14] induced by Thiamet G, a specific inhibitor of O-GlcNAcase which is one of the main enzyme involved in O-GlcNAcylation related post-translational protein modifications [15], could be a new therapeutic target for ADHF. This hypothesis is strengthened by data, showing that thiamet G administrated 12 hours after salt-loading improves left ventricular function, illustrated by the immediate and long-lasting normalization of cardiac output and myocardial tissue perfusion (Fig. 4). Moreover, preliminary data obtained in a limited number of animals shown that delayed thiamet G, i.e. administration 6 days after salt-loading, also improves left ventricular function, which if confirmed, clearly emphasizes the crucial role of post-translational protein modifications in the temporal evolution of ADHF’s pathology.
REFERENCES:
Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

Claims

CLAIMS:
1. A method of treating acute decompensated heart failure in patient in need thereof comprising administering to the patient a therapeutically effective amount of a O- GlcNAcase (OGA) inhibitor.
2. The method of claim 1 wherein the OGA inhibitor improves left ventricular function, and more particularly for improving cardiac output and myocardial tissue perfusion
3. The method of claim 1 wherein the OGA inhibitor of the present invention is selected among Thiazoline derivatives, GlcNAcstatins and related glucoimidazoles, Imminocyclitols, Thioglycoside-naphthalimide hybrids, 1,2,3-Triazole-based derivatives, a-GlcNAc thiosulfonate and Non-carbohydrate-based inhibitors.
4. The method of claim 1 wherein the OGA inhibitor of the present invention is selected from the group consisting of PUGNAc (O-(2-acetamido-2-deoxy-d- glucopyranosylidene) amino-N-phenylcarbamate), 2’-Methyl-a-d-glucopyrano-[2, 1- d]-52’ -thiazoline (NAG-thiazoline, NG), NButGt, Thiamet-G ((3aR,5R,6S,7R,7aR)-2- (ethylamino)-3a,6,7,7a-tetrahydro-5-(hydroxymethyl)-5H-Pyrano[3,2-d]thiazole-6,7- diol), 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas), MK-8719 from
Merck/ Alectos, ASN-120,290 from Asceneuron S.A. and LY-3,372,689 from Eli Lilly.
5. The method of claim 1 wherein the OGA inhibitor is an inhibitor of OGA expression.
6. The method of claim 1 wherein the OGA inhibitor is administered to the patient in one single administration.
PCT/EP2023/065100 2022-06-07 2023-06-06 O-glcnacase inhibition as a treatment for acute decompensated heart failure WO2023237542A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22305820.7 2022-06-07
EP22305820 2022-06-07

Publications (1)

Publication Number Publication Date
WO2023237542A1 true WO2023237542A1 (en) 2023-12-14

Family

ID=82308278

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/065100 WO2023237542A1 (en) 2022-06-07 2023-06-06 O-glcnacase inhibition as a treatment for acute decompensated heart failure

Country Status (1)

Country Link
WO (1) WO2023237542A1 (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
"Bicyclic Picomolar OGA Inhibitors Enable Chemoproteomic Mapping of Its Endogenous Post-translational Modifications", J AM CHEM SOC., vol. 144, no. 2, January 2022 (2022-01-01), pages 832 - 844
"Gene", Database accession no. 10724
"Oral Communication Abstracts", FUNDAMENTAL & CLINICAL PHARMACOLOGY, ELSEVIER, PARIS, FR, vol. 33, 5 June 2019 (2019-06-05), pages 6 - 22, XP071692813, ISSN: 0767-3981, DOI: 10.1111/FCP.12468 *
"Remington's Pharmaceutical-Sciences, Sixteenth Edition", 1980, MACK PUBLISHING CO.
ABOU ZEID F ET AL: "Characterization of cardiac extracellular vesicles upon thiamet G treatment in a rat model of acute decompensated heart failure", ARCHIVES OF CARDIOVASCULAR DISEASES SUPPLEMENTS, ELSEVIER, AMSTERDAM, NL, vol. 13, no. 2, 1 May 2021 (2021-05-01), pages 214 - 215, XP086574202, ISSN: 1878-6480, [retrieved on 20210517], DOI: 10.1016/J.ACVDSP.2021.04.162 *
ALTEEN MATTHEW G ET AL: "Monitoring and modulating O-GlcNAcylation: assays and inhibitors of O-GlcNAc processing enzymes", CURRENT OPINION IN STRUCTURAL BIOLOGY, ELSEVIER LTD, GB, vol. 68, 31 January 2021 (2021-01-31), pages 157 - 165, XP086637562, ISSN: 0959-440X, [retrieved on 20210131], DOI: 10.1016/J.SBI.2020.12.008 *
ALTEEN MGTAN HYVOCADLO DJ: "Monitoring and modulating O-GlcNAcylation: assays and inhibitors of O-GlcNAc processing enzymes", CURR OPIN STRUCT BIOL., vol. 68, June 2021 (2021-06-01), pages 157 - 165, XP086637562, DOI: 10.1016/j.sbi.2020.12.008
BARTOLOME-NEBREDA JMTRABANCO AAVELTER AIBUIJNSTERS P: "O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer's disease and related tauopathies: analysis of the patent literature", EXPERT OPIN THER PAT., vol. 31, no. 12, December 2021 (2021-12-01), pages 1117 - 1154
DASSANAYAKA SUJITH ET AL: "O-GlcNAc and the cardiovascular system", PHARMACOLOGY & THERAPEUTICS, ELSEVIER, GB, vol. 142, no. 1, 25 November 2013 (2013-11-25), pages 62 - 71, XP028661532, ISSN: 0163-7258, DOI: 10.1016/J.PHARMTHERA.2013.11.005 *
DUBOIS-DERUY EBELLIARD AMULDER PBOUVET MSMET-NOCCA CJANEL SLAFONT FBESEME OAMOUYEL PRICHARD V: "Interplay between troponin T phosphorylation and O-N-acetylglucosaminylation in ischaemic heart failure", CARDIOVASC RES., vol. 107, no. 1, July 2015 (2015-07-01), pages 56 - 65
ELBATRAWY AAKIM EJNAM G: "O-GlcNAcase: Emerging Mechanism, Substrate Recognition and Small Molecule Inhibitors", CHEMMEDCHEM, vol. 1S, no. 14, 20 July 2020 (2020-07-20), pages 1244 - 1257
IGUAL MONUNES PSGDA COSTA RMMANTOANI SPTOSTES RCCARVALHO I: "Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA)", CARBOHYDR RES., vol. 471, 1 January 2019 (2019-01-01), pages 43 - 55, XP085560890, DOI: 10.1016/j.carres.2018.10.007
J CHEM INF MODEL., vol. 59, no. 10, 28 October 2019 (2019-10-28), pages 4374 - 4382
J ENZYME INHIB MED CHEM., vol. 33, no. 1, December 2018 (2018-12-01), pages 445 - 452
LACZY BOGLARKA ET AL: "Protein O -GlcNAcylation: a new signaling paradigm for the cardiovascular system", AMERICAN JOURNAL OF PHYSIOLOGY HEART AND CIRCULATORY PHYSIOLOGY, vol. 296, no. 1, 1 January 2009 (2009-01-01), US, pages H13 - H28, XP055981967, ISSN: 0363-6135, DOI: 10.1152/ajpheart.01056.2008 *
MARTINEZ-ILITURRO CMTRABANCO AAROYES JFERNANDEZ ETRESADERN GVEGA JADEL CERRO ADELGADO FGARCIA MOLINA ATOVAR F: "Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders", J MED CHEM., vol. 63, no. 22, 25 November 2020 (2020-11-25), pages 14017 - 14044, XP055769245, DOI: 10.1021/acs.jmedchem.0c01479
NEUROREPORT., vol. 32, no. 17, 8 December 2021 (2021-12-08), pages 1349 - 1356
PAN DGU JHZHANG JHU YLIU FIQBALK, CEKIC NVOCADLO DJDAI CLGONG CX: "Thiamme2-G, a Novel O-GIcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice", J ALZHEIMERS DIS., vol. 81, no. 1, 2021, pages 273 - 286
SABNIS RW: "Benzo[d]thiazol-5-yl Compounds as O-GlcNAcase Inhibitors for Treating Alzheimer's Disease", ACS MED CHEM LETT., vol. 12, no. 6, 18 May 2021 (2021-05-18), pages 947 - 948
SELNICK HGHESS JFTANG CLIU KSCHACHTER JBBALLARD JEMARCUS JKLEIN DJWANG XPEARSON M: "Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.", J MED CHEM., vol. 62, no. 22, 27 November 2019 (2019-11-27), pages 10062 - 10097
SHEN SDONG ZCHEN WWU RLU HYANG QZHANG J.: "Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase", FRONT CHEM., vol. 7, 25 July 2019 (2019-07-25), pages 533
SHEN SDONG ZCHEN WZENG XLU HYANG QZHANG J.: "Modification of the Thioglycosyl-Naphthalimides as Potent and Selective Human O-GlcNAcase Inhibitors", ACS MED CHEM LETT, vol. 9, no. 12, 15 November 2018 (2018-11-15), pages 1241 - 1246
SOULIÉ M. ET AL: "O-GlcNAcase inhibition by Thiamet G opposes acute cardiac decompensation in rats with chronic heart failure", ARCHIVES OF CARDIOVASCULAR DISEASES SUPPLEMENTS, vol. 11, no. 2, 1 April 2019 (2019-04-01), AMSTERDAM, NL, pages 229, XP055981976, ISSN: 1878-6480, DOI: 10.1016/j.acvdsp.2019.02.104 *
TAWADA MFUSHIMI MMASUDA KSUN HUCHIYAMA NKOSUGI YLANE WTJHEN RENDO SKOIKE T: "Discovery of a Novel and Brain-Penetrant O-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization", J MED CHEM., vol. 64, no. 2, 28 January 2021 (2021-01-28), pages 1103 - 1115
WANG X, LI W, MARCUS J, PEARSON M, SONG L, SMITH K, TERRACINA G, LEE J, HONG KK, LU SX, HYDE Z, CHEN SC, KINSLEY D, MELCHOR JP, RU: "MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy. ", J PHARMACOL EXP THER., vol. 374, no. 2, August 2020 (2020-08-01), pages 252 - 263
YANCY CWJESSUP MBOZKURT BBUTLER JCASEY DECOLVIN MMDRAZNER MHFILIPPATOS GSFONAROW GCGIVERTZ MM ET AL.: "2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America", CIRCULATION, vol. 136, 2017, pages e 137 e 161, XP009512425, DOI: 10.1161/CIR.0000000000000509

Similar Documents

Publication Publication Date Title
US20220000869A1 (en) Use of shp2 inhibitors for the treatment of insulin resistance
Mito et al. Curcumin ameliorates cardiac inflammation in rats with autoimmune myocarditis
Zhang et al. Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species
Willis et al. Carboxyl terminus of Hsp70‐interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise
Meng et al. The long noncoding RNA hotair regulates oxidative stress and cardiac myocyte apoptosis during ischemia-reperfusion injury
Altavilla et al. Lipid peroxidation inhibition reduces NF-κB activation and attenuates cerulein-induced pancreatitis
Zhang et al. MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B
Wang et al. microRNA‐454‐mediated NEDD4‐2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications
US20090169540A1 (en) Use Of An Antagonist Of Epac For Treating Human Cardiac Hypertrophy
EP3851100A1 (en) Probenecid for treating decompensated heart failure
Ding et al. Noncoding transcribed ultraconserved region (T‐UCR) UC. 48+ is a novel regulator of high‐fat diet induced myocardial ischemia/reperfusion injury
Wang et al. Protective effect of miR378* on doxorubicin‐induced cardiomyocyte injury via calumenin
Cavalu et al. Ambroxol, a mucolytic agent, boosts HO‐1, suppresses NF‐κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis
Dai et al. Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease
WO2023237542A1 (en) O-glcnacase inhibition as a treatment for acute decompensated heart failure
JP2023508808A (en) Use of the Wnt inhibitor Wnt-C59 in the preparation of therapeutic agents for dilated cardiomyopathy due to SCN5A mutations
Zhang et al. Hydroxysafflor yellow A attenuates carbon tetrachloride-induced hepatic fibrosis in rats by inhibiting Erk5 signaling
JP6473152B2 (en) HDAC inhibitors for suppressing cancer-related cachexia
EP3658157B1 (en) Treatment of heart disease by inhibition of the action of muscle a-kinase anchoring protein (makap)
Guo et al. Salidroside ameliorates pathological cardiac hypertrophy via TLR4‐TAK1‐dependent signaling
Lee et al. Downregulation of SIRT1 and GADD45G genes and left atrial fibrosis induced by right ventricular dependent pacing in a complete atrioventricular block pig model
Liu et al. Aerobic exercise mitigates hippocampal neuronal apoptosis by regulating DAPK1/CDKN2A/REDD1/FoXO1/FasL signaling pathway in D‐galactose‐induced aging mice
EP3071196B1 (en) Hdac inhibitors for suppressing cancer-related cachexia
CN114984220B (en) Application of Mas receptor inhibitor in preparing medicine for preventing and treating acute liver failure
WO2023154850A2 (en) Targeting ire1 kinase and fmrp for prophylaxis, management and treatment of atherosclerosis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23729436

Country of ref document: EP

Kind code of ref document: A1