EP0805818A1 - Neue peptide, ihre herstellung und verwendung - Google Patents
Neue peptide, ihre herstellung und verwendungInfo
- Publication number
- EP0805818A1 EP0805818A1 EP96900898A EP96900898A EP0805818A1 EP 0805818 A1 EP0805818 A1 EP 0805818A1 EP 96900898 A EP96900898 A EP 96900898A EP 96900898 A EP96900898 A EP 96900898A EP 0805818 A1 EP0805818 A1 EP 0805818A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gly
- ala
- new
- pro
- peptide
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
-
- 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
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to new peptides, processes for their preparation and their use in combating diseases.
- ion channel blockers have been used as antiarrhythmics which block transmembrane ion channels (sodium channels, calcium channels and / or potassium channels) which are suitable for therapy of acute cardiac arrhythmias which already exist.
- a new principle is the improvement of cellular coupling.
- An antiarrhythmic peptide AAP10 was proposed as a new principle (Naunyn Schmiedeberg's Arch. Pharmacol. 350, 174 (1994)), which leads to improved cellular coupling, local differences in the action potential duration reduced and the epicardial excitation patterns stabilized.
- this substance shows practically no proarrhythmic risk, but it is effective against ischemia-associated arrhythmias.
- the primary effect of the substance is to reduce the dispersion of the potential duration.
- the invention relates to the compounds of the formula I.
- X preferably denotes a glycine residue.
- Y is preferably a proline residue.
- Z is in particular a halogen atom, preferably iodine, which is in the 2- and preferably in the 3-position.
- the compounds I can be prepared by the methods customary in peptide chemistry. The following processes are particularly suitable for the production thereof:
- Solid phase synthesis on insoluble resins by a modified Merrifield method according to E. Atherston & R.C. Streppard (1989; "Solid phase peptide synthesis, IRL-Press, Oxford) using the Fmoc strategy.
- the amino acid activation can take place via the formation of acid anhydrides, 1-hydroxybenzotriazole esters or pentafluorophenyl esters.
- the invention allows prophylactic therapy of ischemia-associated and age-associated cardiac arrhythmias.
- the substances have no significant proarrhythmic risk in an in vitro experiment.
- the new peptides show a higher potency and a higher achievable maximum effect.
- tyrosine and phthalic anhydride were reacted with one another in glacial acetic acid for 20 h, and the reaction product was reacted with iodine and Hg (II) acetate to give N-phthalyl-L-monoiodtyrosine.
- the protective group was then cleaved off with phenylhydrazine.
- the reaction product was reacted with fluorenylmethoxycarbonyl-N-hydroxysuccinimide in the presence of Na 2 CO 3 , water and acetone. After acidification with HC1, the desired Fmoc iodine tyrosine was obtained.
- Fmoc-proline-OH was combined with 0- ((1H-benzotriazole-1-yD-NNNN-tetramethyluromi- num-tetrafluoroborate (TBTU), 1-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIPEA) in DMF with the peptide
- the protective group was again split off with piperidine, DMF and, after further rinsing, the reaction product was reacted with Fmoc-hydroxyproline-OH as described above.
- OH and Fmoc-Glycino-OH were coupled in.
- the protective group was cleaved with 20% piperidine in DMF, rinsed and added for 6 h
- the peptide (1) was intracoronary to isolated rabbit hearts perfused with constant pressure (70 cm H 2 O) perfused with Tyrode's solution using the Langendorff technique (10 ⁇ 10 ,
- Table 1 Concentration-dependent effect on the dispersion of the epicardial potential duration under the antiarrhythmic peptide AAP10 and the new peptide.
- the better effect of the new peptide becomes particularly clear when one considers the number of values for the epicardial potential duration (ARI) which deviate from the mean value by less than 5 ms.
- the new peptide under control conditions was 54%, on the other hand already 10 " 10 mol / 1 71%, 10" 9 mol / 1 73%, 10 " ⁇ mol / 1 75% 10 " 7 mol / 1 up to 90% of the ARI values in the interval + 5 ms around the mean.
- AAP10 values were achieved over 70% only at concentrations above 10 "8 mol / 1, wherein a maximum of 74% was not th überschrit ⁇ .
- the new substance shows an effect compared to AAP10 even at a lower concentration and a greater maximum achievable effect of up to 90% compared to 74% with AAP10 (% values: n% of epicardial action potentials showed a duration which scattered around the mean value in the range of ⁇ 5 ms, which corresponds to a decrease in the dispersion).
- the new peptide is thus not only more potent, but also more effective than AAPIO with regard to the maximum effect and therefore represents an advance over AAPIO.
- lidocaine belongs to those with a recognized relatively low proarrhythmic risk, while flecainide is generally considered to have a very high proarrhythmic risk.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19500990A DE19500990A1 (de) | 1995-01-14 | 1995-01-14 | Neues Peptid, seine Herstellung und Verwendung |
DE19500990 | 1995-01-14 | ||
PCT/EP1996/000009 WO1996021674A1 (de) | 1995-01-14 | 1996-01-04 | Neue peptide, ihre herstellung und verwendung |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0805818A1 true EP0805818A1 (de) | 1997-11-12 |
Family
ID=7751510
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96900898A Withdrawn EP0805818A1 (de) | 1995-01-14 | 1996-01-04 | Neue peptide, ihre herstellung und verwendung |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0805818A1 (sv) |
JP (1) | JPH11511727A (sv) |
KR (1) | KR19980701397A (sv) |
CN (1) | CN1168142A (sv) |
AU (1) | AU4483696A (sv) |
BR (1) | BR9606756A (sv) |
CA (1) | CA2209496A1 (sv) |
CZ (1) | CZ204897A3 (sv) |
DE (1) | DE19500990A1 (sv) |
FI (1) | FI972965A (sv) |
IL (1) | IL116658A0 (sv) |
NO (1) | NO973230D0 (sv) |
WO (1) | WO1996021674A1 (sv) |
ZA (1) | ZA96239B (sv) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7250397B2 (en) | 2000-02-23 | 2007-07-31 | Zealand Pharma A/S | Antiarrhythmic peptides |
CA2385659C (en) * | 2000-02-23 | 2011-04-19 | Zealand Pharmaceuticals A/S | Novel antiarrhythmic peptides |
US7585839B2 (en) | 2000-02-23 | 2009-09-08 | Zealand Pharma A/S | Medical uses of intercellular communication facilitating compounds |
WO2002077017A2 (en) * | 2001-02-22 | 2002-10-03 | Zealand Pharma A/S | Medical uses of intercellular communication facilitating compounds |
AU2002254033B2 (en) * | 2001-02-22 | 2008-10-16 | Zealand Pharma A/S | Medical uses of intercellular communication facilitating compounds |
US7153822B2 (en) * | 2002-01-29 | 2006-12-26 | Wyeth | Compositions and methods for modulating connexin hemichannels |
CN111303249B (zh) * | 2020-01-02 | 2020-12-18 | 兰州大学 | 一种特异性检测病变胶原蛋白的探针、制备方法及应用 |
-
1995
- 1995-01-14 DE DE19500990A patent/DE19500990A1/de not_active Withdrawn
-
1996
- 1996-01-02 IL IL11665896A patent/IL116658A0/xx unknown
- 1996-01-04 CA CA002209496A patent/CA2209496A1/en not_active Abandoned
- 1996-01-04 WO PCT/EP1996/000009 patent/WO1996021674A1/de not_active Application Discontinuation
- 1996-01-04 CZ CZ972048A patent/CZ204897A3/cs unknown
- 1996-01-04 AU AU44836/96A patent/AU4483696A/en not_active Abandoned
- 1996-01-04 EP EP96900898A patent/EP0805818A1/de not_active Withdrawn
- 1996-01-04 BR BR9606756A patent/BR9606756A/pt not_active Application Discontinuation
- 1996-01-04 CN CN96191447A patent/CN1168142A/zh active Pending
- 1996-01-04 JP JP8521413A patent/JPH11511727A/ja active Pending
- 1996-01-04 KR KR1019970704786A patent/KR19980701397A/ko not_active Application Discontinuation
- 1996-01-12 ZA ZA96239A patent/ZA96239B/xx unknown
-
1997
- 1997-07-11 NO NO973230A patent/NO973230D0/no unknown
- 1997-07-11 FI FI972965A patent/FI972965A/sv unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9621674A1 * |
Also Published As
Publication number | Publication date |
---|---|
BR9606756A (pt) | 1998-01-06 |
CZ204897A3 (en) | 1997-12-17 |
CA2209496A1 (en) | 1996-07-18 |
KR19980701397A (ko) | 1998-05-15 |
AU4483696A (en) | 1996-07-31 |
FI972965A0 (sv) | 1997-07-11 |
JPH11511727A (ja) | 1999-10-12 |
CN1168142A (zh) | 1997-12-17 |
NO973230L (no) | 1997-07-11 |
MX9704796A (es) | 1997-10-31 |
NO973230D0 (no) | 1997-07-11 |
FI972965A (sv) | 1997-07-11 |
IL116658A0 (en) | 1996-05-14 |
WO1996021674A1 (de) | 1996-07-18 |
ZA96239B (en) | 1997-07-14 |
DE19500990A1 (de) | 1996-07-18 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19970702 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE ES FR GB IT LI NL SE |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 19980318 |