WO2024123296A1 - Composé contenant du nicotinamide riboside pour inhiber la formation de kystes et induire l'ovulation dans le syndrome des ovaires polykystiques - Google Patents

Composé contenant du nicotinamide riboside pour inhiber la formation de kystes et induire l'ovulation dans le syndrome des ovaires polykystiques Download PDF

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Publication number
WO2024123296A1
WO2024123296A1 PCT/TR2023/051475 TR2023051475W WO2024123296A1 WO 2024123296 A1 WO2024123296 A1 WO 2024123296A1 TR 2023051475 W TR2023051475 W TR 2023051475W WO 2024123296 A1 WO2024123296 A1 WO 2024123296A1
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Prior art keywords
mitochondrial
pcos
polycystic ovary
ovary syndrome
nicotinamide riboside
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PCT/TR2023/051475
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English (en)
Inventor
Zeliha YETİM
Osman Nuri KELEŞ
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Atatürk Üni̇versi̇tesi̇ Rektörlüğü Bi̇li̇msel Araştirma Projeleri̇ (Bap) Koordi̇nasyon Bi̇ri̇mi̇
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Priority claimed from TR2022/018742 external-priority patent/TR2022018742A2/tr
Application filed by Atatürk Üni̇versi̇tesi̇ Rektörlüğü Bi̇li̇msel Araştirma Projeleri̇ (Bap) Koordi̇nasyon Bi̇ri̇mi̇ filed Critical Atatürk Üni̇versi̇tesi̇ Rektörlüğü Bi̇li̇msel Araştirma Projeleri̇ (Bap) Koordi̇nasyon Bi̇ri̇mi̇
Publication of WO2024123296A1 publication Critical patent/WO2024123296A1/fr

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals

Definitions

  • This invention is to reduce mitochondrial fission, which is an indicator of mitochondrial stress in ovarian follicles in polycystic ovary syndrome with nicotinamide ribosidecontaining composition, and to prevent apopototic cell death due to this, and to eliminate symptoms such as ovarian cystic follicle formation, infertility due to anovulation, impaired hormonal balance (LH/FSH ratio), weight gain in polycystic ovary syndrome.
  • mitochondrial fission is an indicator of mitochondrial stress in ovarian follicles in polycystic ovary syndrome with nicotinamide ribosidecontaining composition
  • PCOS is the most common clinical condition in women of reproductive age, causing oligo- or anovulatory infertility, requiring multidisciplinary follow-up and having multisystemic consequences.
  • increased adrogen production from Theca cells and increase in LH/FSH ratio stand out (1).
  • the negative "feedback" effect of progesterone, estrogen and inhibin on the pituitary is eliminated and FSH release from the pituitary increases (2).
  • Increased FSH levels are necessary for follicular steroidogenesis and follicular growth.
  • FSH granulosa cells convert the androgens produced in theca cells into estrogens and the androgenic dominance in the follicular microenvironment is converted into estrogenic dominance.
  • FSH induces the formation of LH receptors in granulosa cells, which are necessary for ovulation and luteinization.
  • Increased steroidogenesis and elevated estrogen levels in follicular cells increase LH secretion and release mid-cycle through a positive "feedback" effect on the pituitary and hypothalamus.
  • the ovum is expelled and the corpus luteum is formed.
  • mitochondrial fusion and fission dynamics work to functionally protect the mitochondria.
  • An increase in fusion activity leads to mitochondrial elongation by fusion of mitochondria, whereas an increase in fission activity leads to mitochondrial fragmentation by removal of the damaged portion of mitochondria.
  • Mitochondrial fusion helps modify stress by fusing the contents of mildly damaged mitochondria with the contents of intact mitochondria (13). Fusion of mitochondria allows two mitochondrial genomes with different defects within the same organelle to separately encode what is missing in the other. Thus, mitochondrial genomes increased by fusion have the ability to produce all the components necessary for a functional mitochondria (14). Mitochondrial fission helps replace stress by separating the content of slightly damaged mitochondria with the content of intact mitochondria. Damaged mitochondria undergo degradation through mitophagy. If mitochondrial fission occurs at high levels, the cell undergoes autophagy and cell death occurs due to both mitochondrial insufficiency and increased mitophagy (15).
  • Mitochondrial fusion pathways differ between the outer and inner membranes of mitochondria. Known as Mfn1 and Mfn2, mediate fusion between mitochondrial outer membranes, while OPA1 mediates fusion between mitochondrial inner membranes ( 16 ).
  • Dynamin-related protein 1 (Drp1) is a cytoplasmic GTPase and a key player in mitochondrial fission.
  • Drp1 During mitochondrial fission, Drp1 is recruited to the mitochondrial membrane and forms a chain of oligomers that envelop and constrict the mitochondria to form two daughter mitochondria (17).
  • the activity of Drp1 depends on posttranslational modifications such as phosphorylation.
  • DRP 1 (Ser635) is phosphorylated by the cyclin-dependent kinase 1/cyclin B complex, as mitochondrial fission is initiated, Drp1 function is inhibited when DRP1 (Ser656) is phosphorylated by PKA, and mitochondrial dynamics shift toward mitochondrial fusion (18, 19).
  • SIRT1-7 are a family of NAD+-dependent deacetylase enzymes that catalyze post-translational modifications of proteins.
  • SIRT1-7 respond to metabolic challenges, inflammatory signals, hypoxic and oxidative stress in a protective manner (23, 24).
  • SIRT-1 deacetylates and activates PGC-1 alpha, an important transcription factor for mitochondrial gene expression, thereby stimulating mitochondrial biogenesis (25).
  • PGC-1 alpha was found to promote mitochondrial fusion by increasing mitochondrial biogenesis as well as MFN 1 and 2 expression levels and improved cellular survival and mitochondrial functions (26, 27, 28). Furthermore, recent studies found that MFN2 is the substrate for SIRT1 and SIRT1 -mediated MFN1 deacetylation under hypoxic conditions promotes mitochondrial fusion. SIRT1 overexpression has also been proven to reduce Drp1 expression and mitochondrial fission (29, 30). Recently, SIRT1 , a major component of the sirtuin family, has emerged as a sensor and protector of redox status in oocytes, granulosa cells and early embryos (31). In NR-treated mice, increased NAD+ levels were found to lead to SI RT1 -dependent improved mitochondrial function and protect against metabolic damage (32, 33).
  • NAD+ replacement comes to the rescue of women's fertility during reproductive aging (34).
  • NR functions as a precursor of NAD+ and is a recently discovered metabolite of vitamin B3. While NAD itself is difficult to administer directly to humans, its precursors nicotinamide riboside (NR) are promising natural compounds for increasing NAD levels in cells and the body. NR has been shown to have potent antiaging properties to improve glucose metabolism, cardiovascular and neural functions and complications in stem cell maintenance and even to increase longevity in some models (35).
  • NR would normalize ovarian functions by eliminating mitochondrial stress damage that may occur in ovarian tissue and providing improved mitochondrial bioenergetic functions.
  • NR would have positive effects on mitochondrial NAD+ levels, protein acetylation and modulation of mitochondrial dynamics by fission and fusion proteins.
  • Clomiphene citrate is the most effective ovulation-stimulating drug and the first to be used in PCOS patients. This medicine is used under the supervision of a doctor. Although the use of this drug has a high effect on ovulation, pregnancy rates are low.
  • clomiphene citrate is not successful, another alternative drug used in the treatment of PCOS is Letrozole.
  • Letrozole is an aromatose inhibitor. Its effect is to increase endogenous FSH release by inhibiting peripheral estrogen production. In patients with PCOS, this drug increases ovulation due to an increase in FSH release. Although the use of this drug has a high effect on ovulation, pregnancy rates are low, similar to clomiphene citrate. If no success is observed with the use of this drug in the treatment of infertility due to PCOS, alternative recombinant FSH treatment is started (36).
  • Recombinant FSH is used in patients who do not respond to clomiphene citrate and letrozole. It is the most effective drug for the treatment of infertility in patients with PCOS. Complications such as "ovarian hyperstimulation syndrome", a condition in which the whole body is affected as a result of excessive response of the ovaries to the treatment, and multiple pregnancy are particularly important in ovulation treatment in patients who want to become pregnant. Furthermore, pregnancy complications such as gestational diabetes and hypertension may be increased in these patients. In addition, the high cost of this drug is an important disadvantage (36).
  • PCOS polycystic ovary syndrome
  • Mitochondrial dysfunction An emerging link in the pathophysiology of polycystic ovary syndrome. Mitochondrion.
  • Mitochondrial fission factor Drp1 maintains oocyte quality via dynamic rearrangement of multiple organelles. Current Biology, 24(20), 2451-2458.
  • Neuregulin-1 promotes mitochondrial biogenesis, attenuates mitochondrial dysfunction, and prevents hypoxia/reoxygenation injury in neonatal cardiomyocytes. Cell Biochemistry and Function.
  • Nicotinamide riboside attenuates alcohol induced liver injuries via activation of SirT1/PGC-1a/mitochondrial biosynthesis pathway. Redox biology, 17, 89-98.
  • Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Molecular metabolism, 6(8), 819-832.
  • Said invention eliminates the disadvantages described in the state of the art and fulfils the needs.
  • Said invention is the use of nicotinamide riboside in the treatment of polycystic ovary syndrome (PCOS) and the elimination of symptoms such as ovarian cystic follicle formation, infertility due to anovulation, impaired hormonal balance (LH/FSH ratio), and weight gain.
  • PCOS polycystic ovary syndrome
  • Nicotinamide riboside which we use in the treatment of polycystic ovary, is an effective, cheap and easy treatment method. Furthermore, no side effects have been observed in humans at appropriate doses of nicotinamide riboside (10002000 mg/day). In our experimental study, we found that this compound, which is metabolites of vitamin B3, strongly stimulated ovarian follicle development, completely eliminated ovarian cystic follicles and improved the LH/FSH ratio. Based on the above characteristics, it will be a strong alternative to other drugs in the treatment of infertility due to PCOS.
  • FIG. 1 H-E sections of PCOS group.
  • ovarian tissue shows cysts, atresia of antral follicles and corpus luteum with erythrocyte infiltration.
  • FIG. 1 H-E sections of NR group.
  • ovarian tissue shows healthy follicles at various stages of development.
  • P Primary Follicle, AF; Antral follicle, CL; Corpus Luteum.
  • Follicle Hematoxylin-Eosin Staining, A(x10)-B(x20)-C(x40).
  • This invention is the use of nicotinamide riboside in the treatment of polycystic ovary syndrome.
  • NR treatment completely eliminated the cystic structures (Figure 2).
  • Drug treatments increased mitochondrial fusion and reduced fission or prevented mitochondrial stress in granulosa cells.
  • Apoptotic cell death was significantly decreased in granulosa cells due to mitochondrial stress.
  • Treatment significantly increased the number of antral follicles compared to the PCOS group.
  • Drp1 positivity which plays a role in mitochondrial fission, was intense in granulosa cells in the PCOS group, whereas NR treatment decreased Drp1 expressions to the level of healthy subjects.
  • RT-PCR analyses showed that mRNA expression of Drp1 increased and mRNA expression of Mfn1 , which is involved in mitochondrial fusion, decreased in the PCOS group, whereas mRNA expression of Drp1 decreased and mRNA expression of Mfn1 increased in the NR-treated groups.
  • 20 21 -day-old female Sprague-Dawley rats weighing between 40-60 grams were used.
  • Rats were randomly divided into 4 groups. Except for the control group, PCOS model was created by giving Dehydroepiandrosterone (DHEA) for 21 days. NR group received 200 mg/kg NR orally for 17 days. Rats were sacrificed on day 38 and ovaries were evaluated histopathologically, molecularly and biochemically.
  • DHEA Dehydroepiandrosterone
  • Nicotinamide riboside is a metabolite of vitamin B3 naturally found in milk. Nicotinamide riboside is a recently identified NAD+ precursor that is phosphorylated or metabolized to NMN by nicotinamide riboside kinases. Nicotinamide riboside supplementation prolongs life span in yeast and mice and ameliorates metabolic complications associated with a high-fat diet in mice. NR's Cas number is CAS No. 1341-23-7.
  • Nicotinamide riboside was used for the first time in the treatment of polycystic ovary syndrome with positive results. And the following results have been obtained;

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation de nicotinamide riboside dans le traitement du syndrome des ovaires polykystiques (PCOS) pour éliminer les symptômes de PCOS tels que la formation de follicules kystiques ovariens, l'infertilité due à une anovulation, un équilibre hormonal altéré (rapport LH/FSH), et une prise de poids.
PCT/TR2023/051475 2022-12-07 2023-12-06 Composé contenant du nicotinamide riboside pour inhiber la formation de kystes et induire l'ovulation dans le syndrome des ovaires polykystiques WO2024123296A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022018742 2022-12-07
TR2022/018742 TR2022018742A2 (tr) 2022-12-07 Poli̇ki̇sti̇k over sendromuna bağli ki̇st oluşumunu engelleyi̇ci̇ ve ovulasyonu i̇ndükleyi̇ci̇ ni̇koti̇nami̇d ri̇bozi̇d i̇çeri̇kli̇ bi̇leşi̇m

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106715455A (zh) * 2014-06-06 2017-05-24 葛兰素史密斯克莱知识产权（第2 号）有限公司 烟酰胺核苷类似物及其药物组合物和用途
WO2018236814A2 (fr) * 2017-06-19 2018-12-27 Gangadhara Ganapati Dérivés de nicotinamide riboside et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106715455A (zh) * 2014-06-06 2017-05-24 葛兰素史密斯克莱知识产权（第2 号）有限公司 烟酰胺核苷类似物及其药物组合物和用途
WO2018236814A2 (fr) * 2017-06-19 2018-12-27 Gangadhara Ganapati Dérivés de nicotinamide riboside et leurs utilisations

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