EP0090798A1 - A drug based on a substance p antagonist - Google Patents
A drug based on a substance p antagonistInfo
- Publication number
- EP0090798A1 EP0090798A1 EP81902811A EP81902811A EP0090798A1 EP 0090798 A1 EP0090798 A1 EP 0090798A1 EP 81902811 A EP81902811 A EP 81902811A EP 81902811 A EP81902811 A EP 81902811A EP 0090798 A1 EP0090798 A1 EP 0090798A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substance
- trp
- pro
- prophylactically
- antagonist
- 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.)
- Ceased
Links
- 239000003890 substance P antagonist Substances 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title claims abstract description 14
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims abstract description 35
- 101800003906 Substance P Proteins 0.000 claims abstract description 35
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- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 claims abstract description 7
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- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 4
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- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- WBIIPXYJAMICNU-AWEZNQCLSA-N (2s)-5-[amino-[(4-methylphenyl)sulfonylamino]methylidene]azaniumyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate Chemical compound CC1=CC=C(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(O)=O)C=C1 WBIIPXYJAMICNU-AWEZNQCLSA-N 0.000 description 1
- HJMMCTZLXOVMFB-LBPRGKRZSA-N (4-nitrophenyl) (2s)-5-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoate Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)OC1=CC=C([N+]([O-])=O)C=C1 HJMMCTZLXOVMFB-LBPRGKRZSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 229930182820 D-proline Natural products 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
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- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
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- 206010027646 Miosis Diseases 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
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- UEKYKRQIAQHOOZ-KBPBESRZSA-N Pro-Trp Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)[O-])C(=O)[C@@H]1CCC[NH2+]1 UEKYKRQIAQHOOZ-KBPBESRZSA-N 0.000 description 1
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
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- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
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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
Definitions
- the present invention relates to a Substance P antagonist for use in drugs for the prophylactic or therapeutic treatment of diseases released by Substance P, to a method of prophylactically or therapeutically treat ing such a disease, and to a drug for prophylactically. or therapeutically treating inflammations. More specifically, the invention relates to a Substance P antagonist which, in relation to Substance P, has a structure in which L-proline in position 2 has been replaced by D-proline, and L-phenylalanine in position 7 and
- the Substance P antagonist according to this inven tion thus is (D-Pro 2 , D-Trp 7 ' 9 ) Substance P having the formula
- transmitter substances or transmitters consist not only of substances related to adrenaline and acetyl choline (adrenergic and cholinergic nerves, respectively), but also of chemical compounds made up of a series of amino acids joined by peptide bonds, i.e. polypeptides or oligopeptides. In most cases, peptides alone can serve as such neur ⁇ transmitters. A whole series of peptides having this function are already known (see for example the papers published in the New England Journal of Medicine, Vol. 304, pp. 876-885 and 944-951).
- Substance P may be classed among transmitter substances because it has been shown to occur both in nerves transmitting impulses from peripheral parts of the body to the brain (afferents) and nerves extending from the brain (or peripheral ganglia) to different peripheral organs (efferents).
- Substance P is deemed to play an important part in the transmission of pain stimuli from the periphery to the brain.
- the efferent nerves which contain Substance P are apparently capable of stimulating secretion from endocrine glands and causing vasodilation and. contraction of smooth muscle.
- Substance P as synthetized by us has an inhibiting effect on inflammatory conditions in the body, especially the skin, the upper airpassages, the intestine and the eye.
- the present invention therefore relates to the Substance P antagonist (D-Pro 2 , D-Trp 7,9 ) Substance P for use in drugs for the prophylactic or therapeutic treatment of diseases released by substance P.
- the invention concerns a drug for the prophylactic or therapeutic treatment of inflammations, in particular inflammations in the eye.
- the invention relates to a method of prophylatically or therapeutically treating diseases released by Substance P, in particular such diseases as inflammations in the skin, the upper air-passages, the intestine and/or the eye.
- a suitable form for administration of the drug according to this invention is by topical application. Preparation of the Substance P antagonist according to the invention
- L-Arg-D-Pro-L-Lys-L-Pro-L-Gln-L-Gln-D-Trp-L-Phe-D-Trp-L-Leu-L-Met-NH 2 is prepared in a manner that is conventional in this particular field, viz. by the solid phase method described by R.B. Merrifield (J. Am. Chem. Soc., 85, (1963), 2149-2154).
- the solid phase employed is the benzhydrylamine resin described by Monahan et al. (Biochem. Biophys. Res. Com. 48, 1100-1105, (1972)).
- the starting materials employed in the preparation were Boc-Arg-Tos, Boc-Gln-ONp and Boc-Leu from Ferring AB, Malmö, Sweden; D-Pro, Pro, D-Trp and Phe from Merck Darmstadt, Federal Republic of Germany; and the benzhydrylamine resin from Beckman Inc.
- the synthesis was conducted by stages, starting from 5 g BHA resin, 0.51 meq. NH 2 /g, and the amino acids in the compound according to the invention were coupled according to the following schedule
- the peptide content of the material was 86.7%, based on the triacetate.
- the Substance P antagonist used for the present invention was shown to inhibit or cure inflammation by the following experiment.
- a similar inflammatory reaction can be evoked by infrared radiation of a restricted area on the iris.
- the Substance P antagonist according to this invention 90 nmol of the Substance P antagonist according to this invention were injected into the corpus vitrium of the left eye (3 rabbits).
- the right eye was used for control purposes and was given 0.9% saline.
- the irises of both eyes were exposed to infrared radiation.
- the amount of protein in the chamber fluid was measured, and it was found that the so-called light path in the left, treated eye was substantially unchanged, whereas it had been trebled in the right control eye.
- the experiments carried out to induce inflammation by infrared radiation also comprised experiments which showed that the minimum amount of recordable effects was 0.9 nmol of the Substance P antagonist in saline, while the minimum dose for maximum effect was 90 nmol in saline.
- the effect of the antagonist was found to be dose-dependent and rather linear.
- the Substance P antagonist according to the invention was used dissolved in saline for injection and eye drops, but other forms of administration for topical application by spraying, inhalation, instillation, insufflation and injection are also possible. Furthermore, salves, creams, suppositories, tablets, capsules and granulates can be prepared in which the active constituent consists of the Substance P antagonist according to this invention and the remaining ingredients are conventional inert carriers, diluents, excipients etc.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Un antagoniste de substance P est utilisé dans des médicaments pour le traitement prophylactique ou thérapeutique de maladies déclenchées par la substance P. L'antagoniste consiste en (D-Pro2, D-Trp7,9) Substance P ayant la formule$(6,)$. Un médicament pour le traitement prophylactique ou thérapeutique d'inflammations, spécialement dans l'oeil, est également décrit, ce médicament contenant comme substance active l'antagoniste de la substance P mentionné ci-dessus. De plus, un procédé de traitement prophylactique ou thérapeutique d'une maladie déclenchée par la substance P, ou des inflammations, spécialement dans l'oeil, est également décrit. Dans ce procédé, on utilise une quantité thérapeutiquement active de (D-Pro2, B-Trp7,9) Substance P, spécialement sous une forme appropriée à une application locale.A substance P antagonist is used in medicines for the prophylactic or therapeutic treatment of diseases triggered by substance P. The antagonist consists of (D-Pro2, D-Trp7,9) Substance P having the formula $(6,) $. A medicament for the prophylactic or therapeutic treatment of inflammations, especially in the eye, is also described, this medicament containing as active substance the substance P antagonist mentioned above. Additionally, a method of prophylactic or therapeutic treatment of disease triggered by substance P, or inflammations, especially in the eye, is also described. In this process, a therapeutically active amount of (D-Pro2, B-Trp7,9) Substance P is used, especially in a form suitable for local application.
Description
Claims
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/SE1981/000292 WO1983001252A1 (en) | 1981-10-09 | 1981-10-09 | A drug based on a substance p antagonist |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0090798A1 true EP0090798A1 (en) | 1983-10-12 |
Family
ID=20342922
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP81902811A Ceased EP0090798A1 (en) | 1981-10-09 | 1981-10-09 | A drug based on a substance p antagonist |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0090798A1 (en) |
JP (1) | JPS58501675A (en) |
BE (1) | BE894602A (en) |
IT (1) | IT1191028B (en) |
WO (1) | WO1983001252A1 (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3851152T2 (en) * | 1987-09-03 | 1995-01-26 | Univ Georgia | CYCLOSPORINE EYE PRODUCTS. |
FR2719476B1 (en) * | 1994-05-05 | 1997-05-23 | Oreal | Use of a substance P antagonist in a cosmetic composition and composition obtained. |
FR2719474B1 (en) * | 1994-05-05 | 1996-05-31 | Oreal | Use of a substance P antagonist in a cosmetic composition and composition obtained. |
US6203803B1 (en) | 1994-12-14 | 2001-03-20 | Societe L'oreal S.A. | Use of a substance P antagonist in a cosmetic composition, and the composition thus obtained |
FR2728265A1 (en) * | 1994-12-19 | 1996-06-21 | Oreal | USE OF A SUBSTANCE P ANTAGONIST IN A PHARMACEUTICAL COMPOSITION |
EP0737471A3 (en) * | 1995-04-10 | 2000-12-06 | L'oreal | Use of alkaline earth metal salts as TNF-alpha inhibitor in a topical composition and composition obtained therefrom |
FR2732598B1 (en) | 1995-04-10 | 1997-05-09 | Oreal | USE OF ALKALINE EARTH METAL SALT FOR THE TREATMENT OF PRURITUS AND EYE OR PALPEBRAL DYSESTHESIA |
FR2737408B1 (en) * | 1995-07-31 | 1997-09-05 | Oreal | USE OF A BRADYKININE ANTAGONIST IN A COSMETIC, PHARMACEUTICAL OR DERMATOLOGICAL COMPOSITION AND COMPOSITION OBTAINED |
FR2738741B1 (en) * | 1995-09-19 | 1997-12-05 | Oreal | COMPOSITION FOR DYEING KERATINIC FIBERS, CONTAINING AN ANTAGONIST OF SUBSTANCE P |
FR2740341B1 (en) * | 1995-10-26 | 1997-12-19 | Oreal | USE OF LANTHANIDE SALT, TIN, ZINC, MANGANESE, YTTRIUM, COBALT, BARIUM, STRONTIUM IN A SKIN COMPOSITION |
FR2740335B1 (en) * | 1995-10-26 | 1997-12-19 | Oreal | USE OF LANTHANIDE, LITHIUM, TIN, ZINC, MANGANESE OR YTTRIUM SALT AS A SUBSTANCE P ANTAGONIST |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3954640A (en) * | 1973-06-27 | 1976-05-04 | Xerox Corporation | Electrostatic printing inks |
US4052325A (en) * | 1974-12-23 | 1977-10-04 | Eastman Kodak Company | Liquid electrographic developer composition containing redispersible polyester toner and process |
JPS5425833A (en) * | 1977-07-29 | 1979-02-27 | Canon Inc | Electrophotography |
US4202785A (en) * | 1978-05-15 | 1980-05-13 | Eastman Kodak Company | Polyesterionomers having utility in liquid electrographic developer compositions |
JPS5725832A (en) * | 1980-07-23 | 1982-02-10 | Olympus Optical Co | Light source apparatus for endoscope |
-
1981
- 1981-10-09 JP JP50331281A patent/JPS58501675A/en active Pending
- 1981-10-09 WO PCT/SE1981/000292 patent/WO1983001252A1/en not_active Application Discontinuation
- 1981-10-09 EP EP81902811A patent/EP0090798A1/en not_active Ceased
-
1982
- 1982-10-05 BE BE0/209172A patent/BE894602A/en not_active IP Right Cessation
- 1982-10-08 IT IT23678/82A patent/IT1191028B/en active
Non-Patent Citations (1)
Title |
---|
See references of WO8301252A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPS58501675A (en) | 1983-10-06 |
BE894602A (en) | 1983-01-31 |
IT8223678A0 (en) | 1982-10-08 |
IT1191028B (en) | 1988-02-24 |
WO1983001252A1 (en) | 1983-04-14 |
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