WO2022120442A1 - Co-médicaments d'antagonistes du récepteur de type 1 de l'angiotensine ii et inhibiteurs de néprilysine - Google Patents

Co-médicaments d'antagonistes du récepteur de type 1 de l'angiotensine ii et inhibiteurs de néprilysine Download PDF

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WO2022120442A1
WO2022120442A1 PCT/BR2020/050534 BR2020050534W WO2022120442A1 WO 2022120442 A1 WO2022120442 A1 WO 2022120442A1 BR 2020050534 W BR2020050534 W BR 2020050534W WO 2022120442 A1 WO2022120442 A1 WO 2022120442A1
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mixture
codrug
formula
compound
losartan
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PCT/BR2020/050534
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Alessandra MASCARELLO
Cristiano RUCH WERNECK GUIMARÃES
Eloisa ERIKO ISHIKAWA
Hatylas Felype Zaneti De Azevedo
Marcos Antonio FERREIRA JUNIOR
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Aché Laboratórios Farmacêuticos S.A.
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Priority to PCT/BR2020/050534 priority Critical patent/WO2022120442A1/fr
Priority to ARP210103388A priority patent/AR124254A1/es
Publication of WO2022120442A1 publication Critical patent/WO2022120442A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention provides novel codrugs having covalently bound promoieties displaying angiotensin II type 1 receptor (AT1) antagonism and neprilysin (NEP) inhibition and processes of manufacturing thereof.
  • AT1 angiotensin II type 1 receptor
  • NEP neprilysin
  • the invention also includes pharmaceutical compositions and the use of such compounds and methods to treat cardiovascular disorders such as hypertension, heart failure, and kidney diseases.
  • Angiotensin II type 1 (AT1) receptor blockers are drugs employed to control high blood pressure, treat heart failure, and prevent kidney failure. They consist of one of the major therapeutic drug classes recommended for the treatment of essential hypertension. There are currently eight AT1 receptor blockers in the market that are called collectively as sartans.
  • Losartan was the first orally active selective AT1 antagonist, launched in the 1990s. It is an antihypertensive drug administered as a potassium salt in 25 mg, 50 mg and 100 mg tablets. Losartan is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol.
  • Losartan is one of the most prescribed antihypertensive agents in the clinic. It has an oral bioavailability of 33% due to first-pass metabolism to its 10-fold more potent carboxylic acid metabolite, E-3174, formed by oxidation of the C5-hydroxymethyl on the imidazole ring. Losartan produces a biphasic inhibition of the pressor response to Angiotensin II (Ang II), with a transient peak inhibition at 5 min and a gradual decrease over 3 h, suggesting E-3174 could be responsible for the lasting action of losartan.
  • Ang II Angiotensin II
  • cytochrome P450 2C9 (CYP2C9) mediates losartan oxidation to E-3174 ( ) and that CYP2C9 genotypes contribute to interindividual differences in losartan metabolism and, consequently, its antihypertensive effects.
  • the dependence on CYP2C9 metabolism is not desirable from a drug-drug interaction perspective, since hypertensive patients commonly use drugs that are either CYP2C9 substrates (celecoxib, glimepiride, glipizide, rosiglitazone, rosuvastatin, warfarin) or CYP2C9 inhibitors (clopidogrel, amiodarone).
  • E-3174 Drug-drug interactions could lead to insufficient levels of E-3174 and 24-hour blood pressure control.
  • the direct administration of the more active metabolite E-3174 is not possible due to poor oral absorption as the two ionizable acidic groups, one carboxylic acid and one tetrazole group, would hinder its permeability across cell membranes.
  • Neprilysin (neutral endopeptidase, EC 3.4.24.11, NEP) is a zinc-dependent metalloprotease that cleaves and inactivates peptide hormones such as glucagon, enkephalins, substance P, natriuretic peptides, oxytocin, and bradykinin. It is a membrane-bound enzyme found in the endothelial of many tissues, like the brain, kidneys and peripheral vasculature.
  • NEP inhibitors like sacubitrilat, phosphoramidon, thiorphan, and candoxatrilat have already been explored as potential therapeutics in preclinical and clinical studies.
  • a series of mono carboxylic acid small molecule glutaramides based on candoxatrilat have been described elsewhere (Pryde DC, et al. Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides. J Med Chem. 2006;49:4409-24; and Pryde DC, et al. Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Bioorg Med Chem. 2007;15:142-59). Some of the lead molecules display good NEP potency, selectivity, and oral absorption in rodents. Combination of mechanisms of action to treat cardiovascular diseases
  • Combination therapies could provide greater antihypertensive potential than using high doses of a monotherapy, since this could lead to the blocking of several pathways to maintain normal blood pressure levels.
  • polymedication has important limitations such as drug-drug interactions, differences in dosage regimens, inconvenience of taking several pills daily and mismatch between the pharmacokinetics of different drugs.
  • LCZ696 Entresto®
  • NEP inhibitor sacubitril
  • AT1 antagonist valsartan
  • the combined AT1 antagonism and NEP inhibition is superior to blocking only the angiotensin-converting enzyme in patients with chronic heart failure.
  • the twice daily posology of LCZ696 is a limiting factor for this drug, since heart failure patients may experience decreased treatment adherence over the years.
  • co-crystals have several regulatory and large-scale manufacturing hurdles, stability issues, and physicochemical incompatibility between the molecules.
  • Prodrugs are bio-reversible derivatives of drug molecules that need to undergo enzymatic or chemical transformation in vivo to release the pharmacologically active drug. Ten percent (10%) of all pharmaceutical products are prodrugs that were designed to improve oral bioavailability and reduce first-pass metabolism. Most of the sartans (AT1 blockers) are prodrugs.
  • prodrugs are a matter of considerable difficulty in the state of the art and usually requires a thorough evaluation of many promoieties and linkers until obtaining a successful drug candidate.
  • functional groups are amenable to prodrug design, including but not limited to esters, amides, disulfide, carbonates, carbamates, oximes, imines, phosphates, phosphonates and azo bonds.
  • CES Carboxylesterases
  • CES1 Carboxylesterases
  • CES2 preferentially hydrolyzes substrates with a small acyl moiety due to conformational steric hindrance, while CES1 hydrolyzes a variety of bulky substrates offering great opportunities for prodrug design.
  • prodrug formation consists of including pharmacologically inactive transporter groups in the parent compounds to improve specific features of these drugs, such as drug permeation and water solubility.
  • prodrugs a very interesting use of the prodrugs concept is observed in codrugs.
  • This type of compound consists of the chemical association of two active drugs, i.e., the promoiety also has a therapeutic function.
  • the active molecules also need to be released through bond cleavage to perform their therapeutic effects.
  • codrugs There are much fewer examples of codrugs than prodrugs in the art as it is extremely difficult to design a single molecular entity containing two active molecules linked through a cleavable linker that must be cleaved at the right place, at the right time upon oral administration.
  • codrugs pose additional challenges in comparison to prodrugs since the molecular weight of codrugs is anticipated to be much higher and, therefore, achieving drug-like properties to obtain an oral drug is not an easy task. Codrugs are also designed to contain structural features necessary for the pharmacological activity at two targets, but at the same time they need to be susceptible for chemical or metabolic transformation mainly at the cleavable linker so that the two active molecules may be properly delivered at their sites of action.
  • the present invention then comprises the combination of an AT1 antagonist and a NEP inhibitor into a single reciprocal codrug to treat hypertension and other cardiovascular diseases, such as chronic heart failure.
  • This approach offers an opportunity to use the active carboxylic acid metabolite of losartan (E-3174) in the codrug instead of employing losartan itself, representing an improvement since the systemic AT1 antagonism will not be dependent on CYP2C9 metabolism. In other words, patients will not be at a higher risk of drug-drug interactions due to the concomitant use of drugs that are either CYP2C9 substrates or inhibitors.
  • codrug strategy would potentially achieve improved pharmacokinetics, efficacy, dosage convenience, and reduced drug-drug interactions over sartans and even LCZ696, while keeping developability comparable to marketed sartans, i.e., much simpler and less limiting than co-crystals.
  • Acute oral antihypertensive effects of 3b, losartan and 1a in SHR rats were assessed following acute oral administration of 3b (10, 30 and 60 mg/kg), losartan (15 mg/kg), losartan + 1a (15 and 14 mg/kg, respectively) or vehicle to male SHR rats.
  • Data is shown as the mean ⁇ S.E.M. of the SBP, DBP, MAP and HR reduction over time and was analyzed by two-way ANOVA followed by the Holm-Sidak post-hoc test.
  • the invention is related to the general formula compounds (I) shown below:
  • the general formula compounds (I), or appropriate pharmaceutical salts, particularly acid salts, such as sodium or potassium, may be administered alone or in the form of a pharmaceutical composition.
  • the general formula compounds (I), or appropriate pharmaceutical salts may be administered alone or in the form of a pharmaceutical composition.
  • this invention also includes pharmaceutical compositions to treat cardiovascular disorders via AT1 antagonism and/or NEP inhibition, encompassing at least one of the general formula compounds (I) in a therapeutically effective amount, or its appropriate pharmaceutical salts, associated with at least one appropriate pharmaceutical excipient.
  • this invention also includes pharmaceutical compositions to treat cardiovascular disorders via AT1 antagonism and/or NEP inhibition, encompassing at least one compound of the general formula (I) in a therapeutically effective amount, or its appropriate pharmaceutical salts, and with at least one appropriate pharmaceutical acceptable excipient.
  • pharmaceutical acceptable excipients are selected from those well known in the art.
  • pharmaceutical acceptable excipients are selected from at least one of the following: microcrystalline cellulose, hydroxypropylcellulose, crospovidone (water insoluble synthetic cross-linked polyvinylpolypyrrolidone – PVP), magnesium stearate, talc, silica colloidal anhydrous, hypromellose (hydroxypropyl methyl cellulose – HPMC), titanium dioxide, macrogol (polyethylene glycol - PEG) and/or iron oxide.
  • the present invention refers to the (i) use of compounds of the general formula (I) in the manufacturing of a medicament to treat cardiovascular disorders via AT1 antagonism and/or NEP inhibition, particularly cardiovascular disorders such as hypertension, heart failure and kidney diseases or (ii) a method for treatment of cardiovascular disorders via AT1 antagonism and/or NEP inhibition, particularly cardiovascular disorders such as hypertension, heart failure and kidney diseases.
  • the present invention refers to a process for obtaining the compound of general formula(I):
  • NEP inhibitors selected from 1a, 1b, 1c or 1d as indicated in Table 2 below with E-3174 of formula Ia above coupled with the desired linker, using 4-dimethylaminopyridine (DMAP), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), cesium carbonate (Cs 2 CO 3 ) or 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) to generate the active ester, preferably in dichloromethane (DCM) or dimethylformamide (DMF) as solvents. [Table 2]. Selected NEP inhibitors. Compound X R 1a (S) OMe 1b (S) OMe 1c (S) OMe 1d (R) Me
  • the inhibitory (IC50 or Ki) values of 1,039 compounds against NEP were thoroughly analyzed using data from the ChEMBL database. Compounds with pIC50 ⁇ 6.5, molecular weight > 500 g/mol and logP > 5 were removed from the dataset. In addition, molecules containing phosphates, hydroxamic acids or thiols were also filtered out. Finally, molecules containing more than two aromatic rings, and those with two or more acid groups were also removed.
  • LLE Lipophilic ligand efficiency
  • 1a was obtained as previously described by Pryde et al 2007 (59.00 mg; 59.1% yield).
  • the mixture was diluted with EtOAc (50 ml) and H2O (20 ml) and the organic phase was collected and concentrated.
  • the crude product was purified by prep-HPLC.
  • 1b was obtained as previously described by Pryde et al, 2007 (20.00 mg, 31.2% yield).
  • a mixture of 1b (10 mg, 26.4 umol, 1 eq), Losartan (18.2 mg, 39.5 umol, 1.5 eq, HCl), DMAP (8.05 mg, 65.9 umol, 2.5 eq) and EDCI (10.1 mg, 52.7 umol, 2 eq) in dichloromethane (2 mL) was stirred at 25°C for 12 hours.
  • the mixture was diluted with ethyl acetate (50 ml) and water (20 ml) and the organic phase was collected and concentrated to give a crude product which was purified by pre-HPLC.
  • Metabolic stability studies were performed using liver and intestine S9 fractions from humans, as previously described in the state of the art.
  • the codrugs (1 ⁇ M) were incubated with the S9 fractions (1 mg of protein/mL) for 60 min, at 37 °C, with sample collection at 0, 5, 10, 20 30 and 60 minutes.
  • the concentrations of the parent compounds and the active molecules of interest were quantified.
  • the assay buffer was potassium phosphate (100 mM, pH 7.4) and cofactors were NADP (1.3 mM), G6P (3.3 mM), G6PDH (0.4 U/mL), UDPGA (2.5 mM), PAPS (0.1 mM) and MgCl2 (3.3 mM).
  • the results point to the liver as the site of action (cleavage catalyzed by CES1) and not the intestine (cleavage catalyzed by CES2).
  • codrugs 2a, 2b, and 3c did not efficiently converted into the corresponding AT1 and NEP active molecules, demonstrating the inventiveness of the specific structures claimed here. [Table 4]. Conversion of the codrugs into the active molecules of interest in human liver and intestine S9 fractions.
  • NEPi Neprilysin inhibitor.
  • ARB Angiotensin II receptor blockers or AT1 antagonist.
  • ND Not determined due to instability in the assay buffer.
  • the codrugs were incubated with human liver and intestine S9 fraction for 60 min and their conversion to the active molecules was assessed.
  • the active metabolites were: (i) 1a and E-3174 for 3a, 3b and 3c, (ii) 1a and losartan for 2a, (iii) 1b and losartan for 2b, (iv) 1c and E-3174 for 4a.
  • EXAMPLE 4 COMPARISON OF STABILITY OF CODRUG 3b IN LIVER AND INTESTINE S9 FRACTIONS AS WELL AS PLASMA FROM HUMAN AND SPRAGUE-DAWLEY (SD) RATS
  • codrug 3b should demonstrate good stability in different gastrointestinal compartments upon oral administration to humans and rats, partially cleaved in the intestine by CES2 generating mainly the AT1 antagonist E-3174 and then more efficiently cleaved by CES1 in the liver into the two active molecules, E-3174 and 1a.
  • 3b is further cleaved into the active molecules very effectively, while the same does not occur in human plasma, projecting a good plasma exposure for the active molecules after oral administration of 3b to rats and humans, but likely a superior profile in rats.
  • EXAMPLE 5 Oral bioavailability of the AT1 antagonist E-3174 and the NEP inhibitor 1a upon administration of codrug 3b compared to direct administration of losartan, E-3174 and 1a in different rat strains
  • the animals orally dosed with codrug 3b also had considerable bioavailability for the NEP inhibitor 1a (F 10.4% for 1a).
  • codrug 3b was dosed at 10, 30 and 60 mg/kg p.o., same doses planned for the efficacy testing.
  • the plasma exposure of E-3174 upon oral administration of 3b was compared to those of animals directly dosed losartan and E-3174 at 10 mg/kg p.o. and the plasma exposure of 1a upon oral administration of 3b was compared to that of animals directly dosed 1a at 10 mg/kg p.o. (Table 6).
  • Compounds E-3174 and 1a were also dosed intravenously at 1 mg/kg to calculate their oral bioavailability.
  • the plasma exposure of 1a following oral dosing of 3b was also very good, with F values ranging from 9.2 to 18.4%.
  • the AUC for 1a after oral administration of 3b at 60 mg/kg (or 71.02 ⁇ mol/kg) resulted in a similar value for 1a when orally dosed directly at 10 mg/kg (or 25.26 ⁇ mol/kg).
  • Codrug 3b at 10, 30 and 60 mg/kg p.o., the AT1 antagonist losartan alone at 15 mg/kg p.o. and combined with the NEP inhibitor 1a (15 mg/kg p.o. of losartan + 14 mg/kg p.o. of 1a) were evaluated in the SHR model over 24 hours to evaluate their acute antihypertensive effects ( ).
  • the systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) were evaluated at pre-dose, 1, 2, 4, 8 and 24 h after dosing.
  • the mean arterial pressure (MAP) was determined as DBP + 1/3(SBP – DBP) at each time point.
  • the variation ( ⁇ ) of these parameters over time with respect to pre-dose values were obtained, and then the area under the curve (AUC) for each parameter and group were calculated.
  • the codrugs claimed here combine the AT1 antagonist E-3174, losartan’s more active metabolite, and lipophilic efficient NEP inhibitors. By delivering E-3174, the codrugs then bypass the CYP2C9-mediated conversion of losartan to E-3174, mitigating CYP2C9 polymorphism, and reducing the risk of drug-drug interactions with CYP2C9 substrates or inhibitors.
  • the codrugs in the present invention would also mitigate the potential formation of losartan-derived reactive metabolites, avoiding the risk of idiosyncratic drug ⁇ induced liver injury. It should be noted that the codrugs would offer benefits not only over losartan but also over E-3174, as this active metabolite, if dosed directly, would be poorly absorbed.
  • the codrugs of the present invention are able to do all that, while providing meaningful plasma concentrations of lipophilic efficient NEP inhibitors for optimal synergy with the AT1 antagonist.
  • the present invention clearly demonstrates the concept of codrugs of an AT1 antagonist and a NEP inhibitor as a viable option over standalone AT1 blocking therapies and their fixed-dose combinations with NEP inhibitors, representing a significant advance in the state of the art to obtain an once-daily, dual-acting codrug clinical candidate for the treatment of hypertension and heart failure.

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Abstract

L'invention concerne de nouveaux co-médicaments présentant des fragments liés de manière covalente affichant l'antagonisme du récepteur de type 1 de l'angiotensine II (AT1) et l'inhibition de néprilysine (NEP), ainsi que des procédés de fabrication associés. L'invention concerne également des compositions pharmaceutiques et l'utilisation de tels composés et de tels procédés pour traiter des troubles cardiovasculaires tels que l'hypertension, l'insuffisance cardiaque, ainsi que des maladies rénales.
PCT/BR2020/050534 2020-12-10 2020-12-10 Co-médicaments d'antagonistes du récepteur de type 1 de l'angiotensine ii et inhibiteurs de néprilysine WO2022120442A1 (fr)

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PCT/BR2020/050534 WO2022120442A1 (fr) 2020-12-10 2020-12-10 Co-médicaments d'antagonistes du récepteur de type 1 de l'angiotensine ii et inhibiteurs de néprilysine
ARP210103388A AR124254A1 (es) 2020-12-10 2021-12-06 Codrogas de antagonistas del receptor tipo 1 de angiotensina ii e inhibidores de neprilisina

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009076288A1 (fr) * 2007-12-11 2009-06-18 Theravance, Inc. Dérivés de benzimidazole à double effet et leur utilisation en tant qu'antihypertenseurs
WO2010011821A2 (fr) * 2008-07-24 2010-01-28 Theravance, Inc. Agents anti-hypertensifs à double action
WO2011011232A1 (fr) * 2009-07-22 2011-01-27 Theravance, Inc. Agents antihypertenseurs à double action à base d'oxazole
WO2015030711A1 (fr) * 2013-08-26 2015-03-05 Novartis Ag Nouvelle utilisation
WO2017006254A1 (fr) * 2015-07-08 2017-01-12 Novartis Ag Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009076288A1 (fr) * 2007-12-11 2009-06-18 Theravance, Inc. Dérivés de benzimidazole à double effet et leur utilisation en tant qu'antihypertenseurs
WO2010011821A2 (fr) * 2008-07-24 2010-01-28 Theravance, Inc. Agents anti-hypertensifs à double action
WO2011011232A1 (fr) * 2009-07-22 2011-01-27 Theravance, Inc. Agents antihypertenseurs à double action à base d'oxazole
WO2015030711A1 (fr) * 2013-08-26 2015-03-05 Novartis Ag Nouvelle utilisation
WO2017006254A1 (fr) * 2015-07-08 2017-01-12 Novartis Ag Combinaison de médicaments comprenant un antagoniste du récepteur de l'angiotensine ii, un inhibiteur d'endopeptidase neutre et un antagoniste du récepteur de minéralocorticoïdes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MCKINNELL R. MURRAY, FATHEREE PAUL, CHOI SEOK-KI, GENDRON ROLAND, JENDZA KEITH, OLSON BLAIR BROOKE, BUDMAN JOE, HILL CRAIG M., HEG: "Discovery of TD-0212, an Orally Active Dual Pharmacology AT 1 Antagonist and Neprilysin Inhibitor (ARNI)", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 10, no. 1, 10 January 2019 (2019-01-10), US , pages 86 - 91, XP055947804, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.8b00462 *
SCOTT A. HUBERS ET AL.: "Angiotensin Receptor Antagonism and Neprilysin Inhibition", CIRCULATION, vol. 133, 15 March 2016 (2016-03-15), pages 1115 - 1124, XP055701619, DOI: 10.1161/CIRCULATIONAHA.115.018622 *
SUN JINGCHAO, XU WENJIE, HUA HUAIJIE, XIAO YING, CHEN XIAOYAN, GAO ZHIWEI, LI SONG, JING XIAOLONG, DU FRANK, SUN GUOFENG: "Pharmacodynamic and pharmacokinetic effects of S086, a novel angiotensin receptor neprilysin inhibitor", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, FR, vol. 129, 1 September 2020 (2020-09-01), FR , pages 110410, XP055793583, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2020.110410 *

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