US20110312895A1 - Dipeptide mimetics of ngf and bdnf neurotrophins - Google Patents

Dipeptide mimetics of ngf and bdnf neurotrophins Download PDF

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US20110312895A1
US20110312895A1 US13/148,830 US201013148830A US2011312895A1 US 20110312895 A1 US20110312895 A1 US 20110312895A1 US 201013148830 A US201013148830 A US 201013148830A US 2011312895 A1 US2011312895 A1 US 2011312895A1
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Sergey Borisovich Seredenin
Tatyana Alexandrovna Gudasheva
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Uchrezhdenie Rossiiskoi Akademii Meditsynskikh Nauk Nauchno-Issledovatelsky Institut Farmakologii Imeni Vvzakusova Ramn
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Uchrezhdenie Rossiiskoi Akademii Meditsynskikh Nauk Nauchno-Issledovatelsky Institut Farmakologii Imeni Vvzakusova Ramn
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Assigned to UCHREZHDENIE ROSSIISKOI AKADEMII MEDITSYNSKIKH NAUK NAUCHNO-ISSLEDOVATELSKY INSTITUT FARMAKOLOGII IMENI V.V.ZAKUSOVA RAMN reassignment UCHREZHDENIE ROSSIISKOI AKADEMII MEDITSYNSKIKH NAUK NAUCHNO-ISSLEDOVATELSKY INSTITUT FARMAKOLOGII IMENI V.V.ZAKUSOVA RAMN ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUDASHEVA, TATYANA ALEXANDROVNA, SEREDENIN, SERGEY BORISOVICH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C07K5/06069—Ser-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • FIG. 1.7 Effects of the peptide GSB-106 on the survival of HT22 cells under oxidative stress conditions.
  • Lane 1 heat shock (42° C., 1 h); lane 2: NGF (100 ng/ml); lane 3: control; lane 4: GK-1 (10 ⁇ 5 M); lane 5: GK-1 (10 ⁇ 8 M); lane 6: GK-2 (10 ⁇ 5 M); lane 7: GK-2 (10 ⁇ 8 M); lane 8: GK-1+GK-2 (10 ⁇ 5 M).
  • FIG. 2.2 Reduction of neurological deficit in post-ischemic rats treated with GK-2 (1 mg/kg i.p.).
  • A 4 days after ischemia;
  • B 7 days after ischemia, the limb-placing test.
  • FIG. 2.12 Effects of GSB-106 (1 mg/kg i.p., 24 hrs before the second landing) on the behavioral dispair in mice. *p ⁇ 0.05 versus control according to the Mann-Whitney U-test.
  • the protective groups were removed in accordance with the nature of a particular group, namely, the carbobenzoxyl groups and benzyl groups were removed by hydrogenolysis by passing hydrogen in methanol over a 10% palladium on carbon, the t-butyloxycarbonyl groups and t-butyl groups were removed in an acidic medium by HCl in dioxane or by anhydrous trifluoracetic acid.
  • Elemental analysis data for the compounds in regard to the relative percentages of C, H and N may deviate from theoretical values by not more than 0.4%.
  • DMEM growth medium Hank's medium, fetal calf serum (FBS), phosphate-buffered saline (PBS), poly-L-lysine, 3-(4,5-dimethylthiazol-2-yl)-2,5-tetrazolium hydrobromide (MTT), dimethylsulfoxide (DMSO) were from ICN. 130 kDa Nerve growth factor from the mouse submandibular gland (NGF-7s) was from Sigma.
  • FBS fetal calf serum
  • PBS phosphate-buffered saline
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-tetrazolium hydrobromide
  • DMSO dimethylsulfoxide
  • the experiments employed 96-, 48-, and 6-well culture plates.
  • the wells were treated with poly-L-lysine (0.1 mg/ml) in sterile deionized water ( ⁇ Q, Millipore) for 30 min followed by washing with sterile water (3 ⁇ ) and drying in a laminar flow box at room temperature.
  • the cells were plated at a density of 3.5 ⁇ 10 3 per well in DMEM with 5% FBS. NGF (100 ng/ml) was added at the time of plating and every 48 hours thereafter. All the experiments using differentiated PC12 cells were performed at day 6 of growth.
  • MTT is a water soluble tetrazolium salt of yellow color which readily permeates cells. In living cells, MTT is converted into water insoluble formazan crystals of violet color.
  • MTT solution 0.5 mg/ml
  • DMSO DMSO
  • PC-12 cells When supplemented with nerve growth factors, PC-12 cells are able to differentiate to a neuronal type, which is the reason behind their use in the studies designed to evaluate the differentiation-inducing activity of various drugs.
  • GK-1 through GK-4 were found not to induce the differentiation of PC-12 cells at any concentration tested.
  • GK-1 at 10 ⁇ 5 M decreased the differentiation-promoting effect of NGF by 50% (this result was obtained by counting the numbers of differentiated and undifferentiated cells).
  • GK-5 showed a differentiation-promoting effect at 10 ⁇ 6 M and 10 ⁇ 5 M.
  • this peptide may be effective in cases where visceral innervation is impaired.
  • GK-2 at concentrations from 10 ⁇ 8 to 10 ⁇ 5 M as well as NGF at a concentration of 100 ng/ml added at the time of plating and every 24 hours thereafter for a total of 10 days were found to improve the viability of neurons in the absence of any damaging factors (Table 1.2).
  • GK-1 (10 ⁇ 5 M) eliminated the neuroprotective effect of GK-2.
  • GK-2 had a significant protective effect in a cellular model of Parkinson's disease. This effect was displayed only at 10 ⁇ 5 M when GK-2 was added concurrently with MPTP, however, when added 24 hours prior to MPTP, it was active at both 10 ⁇ 5 M and 10 ⁇ 8 M ( FIGS. 1.9 , 1 . 10 ).
  • the peptide GK-5 was inactive in this test.
  • the peptides GK-2, GK-4 and GSB-106 demonstrated a protective effect against glutamate cytotoxicity in cultured HT-22 cells when added 24 hours prior to glutamate ( FIG. 1.12 , Table 1.12).
  • the BDNF mimetic GSB-106 was active in the concentration range of 10 ⁇ 8 M to 10 ⁇ 5 M, with its effect increasing in extent with decreasing concentrations.
  • GK-1 at concentrations of 10 ⁇ 8 M and 10 ⁇ 5 M had no effect on the amount of these proteins.
  • GK-2 at concentrations of 10 ⁇ 8 M and 10 ⁇ 5 M induced an increase in the levels of Hsp70 and Hsp32 proteins ( FIGS. 1.13 , 1 . 14 ).
  • GK-1 (10 ⁇ 5 M) was added 30 minutes before GK-2 no increase in the amount of Hsp32 and Hsp70 was observed ( FIGS. 1.13 , 1 . 14 ).
  • the claimed compounds having a neuroptotective activity identified in the in vitro experiments were also characterized in animal models of neurodegenerative diseases such as stroke, cerebral ischemia, Parkinson's disease, Alzheimer disease.
  • the compound was chosen most active with respect to its neuroptotective effects, namely GK-2, a dimeric NGF loop 4 mimetic.
  • test compound GK-2 can be useful in the treatment of both ischemic and hemorrhagic insults. Thus it would make it possible to undertake the treatment of stroke patients even before the differential diagnostics, i.e. at the most important first stages of the disease.
  • FIG. 2.5 shows that the ligation led to a reduced horizontal motor activity in the open field test. GK-2 restored it to the level found in the sham-operated rats. The ligation also led to a reduced vertical motor activity in the open field test, and GK-2 restored it to the level found in the sham-operated rats.
  • FIG. 2.7 In the object exploration test, the ligation resulted in a reduced total object smelling time ( FIG. 2.7 ). The lower level of this index in the ligation group was due to a reduction in the object exploration during the first minute of testing ( FIG. 2.8 ).
  • FIGS. 2.7 and 2 . 8 also show that the ligation group treated with GK-2 was not different from the sham-operated rats, i.e. GK-2 prevented the decline in these measures induced by the ligation. Thus, GK-2 was able to improve the episodic memory in rats and their ability to perceive novelty.
  • test compound was administered intraperitoneally to male C57B1/6 mice weighing 22-25 g at a preselected dose of 1.0 mg/kg at 24 hours prior to the MPTP injection (30 mg/kg i.p.).
  • the animals were placed in the open-field device 60 min after the MPTP injection. Animal's horizontal and vertical motor activities were monitored for 2 minutes.
  • Passive control group was represented by animals treated with distilled water instead of MPTP.
  • Active control group was represented by animals treated with distilled water instead of GK-2 followed by MPTP.
  • the treatment group was treated with GK-2 followed by MPTP.
  • Statistical data treatment was carried out using the Mann-Whitney U-test. The results are shown in Table 2.11 below.
  • Oral stereotypy (smelling, licking, biting) was recorded using the following scoring system: 1, isolated stereotyped movements; 2, brief (episodic) stereotypy; 3, continuous stereotypy.
  • To record a continuous, deep and very intensive stereotypy an additional score of 4 was introduced to the existing scale (deep stereotypy was characterized in that the animals were unresponsive to external stimuli).
  • Stereotypy was recorded once for 5 min within a period of 60 min. At the end of an experiment the cumulative score for each animal was calculated for the entire testing period. Differences between experimental groups were assessed according to the Mann-Whitney U-test. The data were expressed as the median value ⁇ interquartile interval ( FIGS. 2.10 ).
  • the first injection of the test compound (1 mg/kg i.p.) in the treatment group or of distilled water in the control group was made 2 hours after the transection. Further injections were made every 48 hours. In the course of the experiment each animal received 7 injections of the test compound.
  • test compound could prevent the scopolamine-induced working memory impairments under pretreatment conditions.

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US13/148,830 2009-02-16 2010-02-15 Dipeptide mimetics of ngf and bdnf neurotrophins Abandoned US20110312895A1 (en)

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RU2009105176A RU2410392C2 (ru) 2009-02-16 2009-02-16 Дипептидные миметики нейротрофинов ngf и bdnf
RU2009105176 2009-02-16
PCT/RU2010/000067 WO2010093284A1 (ru) 2009-02-16 2010-02-15 Дипептидные миметики нейротрофинов ngf и bdnf

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MX340233B (es) * 2010-08-31 2016-07-01 Bionure Farma S L Agonistas de receptores de neurotrofina y sus usos como medicamentos.
RU2613184C2 (ru) * 2013-05-17 2017-03-15 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" (ФГБНУ "НИИ фармакологии имени В.В. Закусова") Вещества, обладающие ангиогенной активностью
RU2613314C2 (ru) * 2013-06-28 2017-03-15 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Малые молекулы с NGF-подобной активностью, обладающие антидиабетическими свойствами
RU2625752C2 (ru) * 2013-11-19 2017-07-18 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Вещество, обладающее антиангиогенной активностью
RU2559880C1 (ru) * 2014-06-18 2015-08-20 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Замещенный бисдипептид с нейропротективным и антидепрессивным эффектом
RU2678203C2 (ru) * 2017-05-30 2019-01-24 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Фармацевтическая композиция нейропротекторного действия для парентерального применения на основе гексаметилендиамида бис-(N-моносукцинил-L-глутамил-L-лизина) в лиофилизированной лекарственной форме
RU2693479C2 (ru) * 2017-11-20 2019-07-03 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Средство, обладающее антидиабетической активностью
RU2697254C1 (ru) * 2018-02-28 2019-08-13 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Фармацевтическая композиция на основе гексаметилендиамида бис-(N-моносукцинил-L-серил-L-лизина) (ГСБ-106)
RU2740754C1 (ru) * 2018-11-13 2021-01-20 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Фармацевтическая композиция нейропротекторного действия для перорального применения на основе гексаметиленамид бис-(N-моносукцинил-L-глутамил-L-лизина) (варианты), выполненная в виде таблетки, диспергируемой в полости рта
RU2707301C1 (ru) * 2019-05-17 2019-11-26 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Низкомолекулярный миметик BDNF как средство для лечения опиоидной зависимости
CN111647003B (zh) * 2020-06-08 2022-06-21 中国科学院昆明植物研究所 三环氧六氢色酮a及其药物组合物和其应用

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EP2397488A1 (de) 2011-12-21
WO2010093284A1 (ru) 2010-08-19
RU2410392C2 (ru) 2011-01-27
EP2397488A4 (de) 2014-03-19
CN102365294A (zh) 2012-02-29
RU2009105176A (ru) 2010-08-27
EP2397488B1 (de) 2019-03-27
CN102365294B (zh) 2016-02-17
US9683014B2 (en) 2017-06-20
US20150111828A1 (en) 2015-04-23

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