EP0531342A1 - Ringförmige und geradkettige therapeutische peptide - Google Patents
Ringförmige und geradkettige therapeutische peptideInfo
- Publication number
- EP0531342A1 EP0531342A1 EP91909510A EP91909510A EP0531342A1 EP 0531342 A1 EP0531342 A1 EP 0531342A1 EP 91909510 A EP91909510 A EP 91909510A EP 91909510 A EP91909510 A EP 91909510A EP 0531342 A1 EP0531342 A1 EP 0531342A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ala
- leu
- phe
- trp
- val
- 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- Withdrawn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
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
- C07K7/086—Bombesin; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to peptides useful for treatment of benign or malignant proliferation of tissue.
- the amphibian peptide bombesin pGlu-Gln-Arg- Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 (Anastasi et al., Experientia 22:166-167 (1971)), is closely related to the mammalian gastrin-releasing peptides (GRP), e.g., the porcine GRP, H 2 N- Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr- Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala- Val-Gly-His-Leu-Met-(NH 2 ) (McDonald et al., Biochem.
- GRP mammalian gastrin-releasing peptides
- Bombesin exhibits both direct and indirect effects on the gastrointestinal tract, including the release of hormones and the stimulation of pancreatic, gastric, an intestinal secretion and of intestinal mobility.
- Gastrin and cholecystokinin (CCK) which are released by bombesin, have been shown to play a role in the maintenance of normal gastrointestinal mucosa as well a in augmenting growth of normal and neoplastic tissues.
- Nle H 2 N-CH-C00H (norleucine)
- R right (D) configuration
- S left (L) configuration
- racemate equal mix of R and S
- 3-methyl-His methyl (CH 3 ) group on nitrogen at positions 1 or 3 of Histidine:
- the invention features a linear or a cyclic therapeutic peptide, which includes between seven and ten amino acid residues, inclusive, and which is an analog of one of the following naturally occurring peptides which terminate at the carboxy-terminus with a Met residue: (a) litorin; (b) the ten amino acid carboxy-terminal region of mammalian GRP, neuromedin B, or neuromedin C; and (c) the ten amino acid carboxy-terminal region of amphibian bombesin, which is an analog of the formula:
- a 2 Gly, D- or L- isomer of any of pGlu, Ala, Val, Gin, Asn, Leu, lie,
- a 6 Sar, Gly or the D-isomer of any Ala, N-methyl-Ala, Val, Gin, Asn, Leu, lie, p-X-Phe
- X H, F, Cl, Br, N0 2 , OH, or CH 3
- Trp Cys, or /3-Nal
- a 7 1-methyl-His, 3-methyl-His, His, Lys, Asp, or Glu
- a 8 Leu, lie, Val, Nle, a-aminobutyric acid, p-X-Phe
- each R j ⁇ and R 2 independently, is H, C 1 _ 12 alkyl, c 7 _ 10 phenylalkyl, COE j ⁇ (where E ⁇ is C 1 _ 20 alkyl, c 3 _ 20 alkenyl, C 3 - 20 aiki ⁇ y 1 - phenyl, naphthyl, or C 7 _ 10 phenylalkyl), or c ⁇ c i 2 acy1 ' and R ⁇ and R 2 are b °nded to the N-terminal amino acid of the peptide; provided that when one of R j or R 2 is COE j , the other must be H; and R 3 is H, NH 2 , C ⁇ - 12 7 - ⁇ o phenylalkyl, or C 3 _ 20 naphthylalkyl; and further provided that, if A 0 is present, A 1 cannot be pGlu; and, if A 0 or A 1 is present
- a 3 can be bonded to A 9 to form a cyclized peptide; and provided that where A 0 is deleted and A 1 is Asp or Glu, or where A and A 1 are deleted and A is Asp or Glu, either A 1 or A 2 can be bonded with A 7 or A 8 , where A 7 or A 8 is Lys, or where A 0 is deleted and A 1 is
- Lys or A 0 and A 1 are deleted and A 2 is Lys, either A 1 or
- a 2 can be bonded to A 7 or A 8 , where A 7 or A 8 is Asp or Glu; and further provided that either one of A 1 or A 2 can be Cys and can be bonded through a disulfide bridge with either A 8 or A 9 , provided that either one of A 8 or A 9 can be Cys and can be bonded through a disulfide bridge with either A 1 or A 2 ; and further provided that where A 0 and A 1 are deleted and A 6 is D-Ala, A 8 -A 9 cannot be
- R ⁇ or R 2 when either of R ⁇ or R 2 is an aliphatic, aromatic, or lipophilic group, the .in vivo activity can be long lasting, and delivery of the compounds of the invention to the target tissue can be facilitated.
- a 1 pGlu, D-Phe, D-Ala, D-/3-Nal, D-Cpa, D-Asn, Cys, or is deleted;
- a 2 pGlu, Asn, Gin, His, 1-methyl-His, 3-methyl-His, Cys, or is deleted;
- a 3 Trp;
- a 6 Sar, Gly, D-Phe, or D-Ala;
- a 9 L-isomer of any of Met, Leu, lie, Nle, Phe, or Cys.
- Examples of preferred peptide analogs are: pGlu-Gln-Trp-Ala-Val-Gly-His-Leu-Leu-NH 2 ; D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Leu-NH 2 ;
- the invention also features a linear or a cyclic therapeutic peptide, which includes between seven and ten amino acid residues, inclusive, and which is an analog of one of the following naturally occurring peptides which terminate at the carboxy-terminus with a Met residue: (a) litorin; (b) the ten amino acid carboxy-terminal region of mammalian GRP, neuromedin B, or neuromedin C; and (c) the ten amino acid carboxy-terminal region of amphibian bombesin, and the analog is an agonist of one of these naturally occurring peptides.
- the analog may be an agonist or a partial agonist of the naturally occurring biologically active peptide; preferably, the analog is at least 25%, more preferably 50% or 75%, homologous with a region of the naturally occurring peptide.
- an "agonist” mimics or enhances the biological effect of the natural peptide on its target cell and a "partial agonist” mimics or enhances the biological effect of the natural peptide, but to a lesser extent than an agonist.
- Biological effect is measured by the effect of the natural peptide in one of two systems: an in vitro pancreatic amylase release assay and an in vitro 3T3 fibroblast cell division system, both of which are described in European Patent Application 88308916.6, hereby incorporated by reference.
- An agonist will stimulate the effect of the natural peptide on either amylase release from pancreatic cells or fibroblast cell division by 100%, whereas a partial agonist will have a lesser stimulatory effect, i.e., ranging between 0-99%.
- Peptides of the invention are useful for treating non-malignant proliferative disease in a human patient, e.g., the proliferation of smooth muscle.
- Peptides of the invention are also useful for treating cancer in a human patient, particularly for the treatment of prostatic, colon, breast, pancreatic, or lung cancer.
- peptides of the invention may be used to suppress appetite, to stimulate pancreatic secretion, or to suppress a craving for alcohol.
- Analogs of the invention can be provided in the form of pharmaceutically acceptable salts.
- preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluene sulfonic, trifluoroacetic, or pa oic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as the hydrohalic acids,e.g., hydrochloric acid, sulfuric acid or phosphoric acid.
- hydrohalic acids e.g., hydrochloric acid, sulfuric acid or phosphoric acid.
- Fig. 1 is the amino acid sequences of naturally occurring peptides of which peptides of the invention are analogs. We now describe the structure, synthesis, and use of the preferred embodiments of the invention. Structure
- Peptides of the invention are derived from one of the sequences shown in Fig. 1, which represent the sequences, or portions thereof, of naturally-occurring peptides. Bombesin, neuromedin B, neuromedin C, litorin, and GRP analogs of the invention are described in Coy et al., U.S. Patent Application Serial No. 502,438, filed March 30, 1990, which is a continuation-in-part of U.S. Patent Application Serial No. 397,169, filed August 21, 1989, which is a continuation-in-part of U.S. Patent Application Serial No. 376,555, filed July 7, 1989, and U.S. Patent Application Serial Number 394,727, filed August 16, 1989, both of which are continuation-in-parts of U.S.
- D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Leu-NH 2 follows.
- Other bombesin or GRP agonists can be prepared by making appropriate modifications of the following synthetic method. 1) Incorporation of alpha-t-butoxycarbonyl (BOC)- leucine on 4-methyl benzhydrylamine.
- 4-methyl benzhydryla ine-polystyrene resin (Bachem, Inc.) (0.72 meq/g) in the chloride ion form is placed in the reaction vessel of an ACT200 peptide synthesizer (Advanced Chem Tech, Inc.) programmed to perform the following reaction cycle: (a) methylene chloride; (b) 10% triethylamine in chloroform; (c) methylene chloride; and (d) dimethylformide.
- the neutralized resin is mixed with alpha-t-butoxycarbonyl (BOC)-leucine and diisopropylcarbodiimide (3 molar eq each) in methylene chlrodie for 1 hour.
- the resulting amino acid resin is washed on the synthesizer with dimethylformamide and treated with 5% acetic anhydride in dimethylformamide for 5 min. Then it is washed with dimethylformamide and methylene chloride. 2) Couplings of the remaining amino acids.
- the peptide synthesizer is programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid (TFA) in methylene chloride (2 times for 5 and 25 min. each) ; (c) methylene chloride; (d) isopropyl alcohol; (e) 10% triethylamine in chloroform; and (f) methylene chloride.
- TFA trifluoroacetic acid
- the peptide resin described above (1.41 g) is mixed with anisole (5 ml) , dithioerythreitol (50mg) , and anhydrous hydrogen fluoride (25 ml) at 0°c for one hour. Excess hydrogen fluoride is evaporated rapidly under a stream of dry nitrogen, and the residue is washed in ether. Crude peptide is dissolved in 100ml of 4M acetic acid and the solution is then evaporated under reduced pressure. The crude peptide is dissolved in minimum volume of methanol/water and triturated with ethyl acetate. The triturated peptide is applied to a column (9.4mm I.D.
- Peptides of the invention may be cyclized as follows.
- Crude peptide acid obtained from peptide-resin ester by HF cleavage is dissolved in DMF (0.1%-1% concentration), treaed with condensing agent (e.g., BOP reagent, DEPC, DPPA, or any other condensing agent) followed by base (e.g., triethylamine, diisopropylethylamine) at room temperature for 1-3 days. Solvent is removed in vacuum to dryness. The residue is purified by HPLC, according to conventional procedures.
- condensing agent e.g., BOP reagent, DEPC, DPPA, or any other condensing agent
- base e.g., triethylamine, diisopropylethylamine
- Analogs of the invention may prevent or inhibit the growth of cancer cells, or may prevent the proliferation of non-malignant tissue, by acting as agonists or partial agonists; i.e., the analog may fully or partially mimic or enhance the biological effect of the natural peptide on a target cell.
- One possible mechanism of analog inhibition of growth of cancer cells is suggested in Bunn et al. (1990, Proc. Nat. Aca. Sci. 87:2162) , in which calcium ion flux was measured in CHO cells after administration of one or more neuropeptides. Bunn et al.
- Analogs of the invention are useful for treating colon, prostatic, breast, pancreatic, or lung cancer, for preventing the proliferation of smooth muscle, to suppress appetite, to stimulate pancreatic secretion, or to suppress a craving for alcohol.
- Analogs of the invention are administered to a mammal, particularly a human, in one of the traditional modes (e.g., orally, parenterally, transdermally, or trans ucosally) , in a sustained release formulation using a biodegradable biocompatible polymer, or by on-site delivery using micelles, gels and liposomes, or rectally (e.g., by suppository or enema) .
- the analogs can be administered to a human patient in a dosage of 0.25 mg/kg/day to 5 mg/kg/day.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52022690A | 1990-05-09 | 1990-05-09 | |
US520226 | 1990-05-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0531342A1 true EP0531342A1 (de) | 1993-03-17 |
EP0531342A4 EP0531342A4 (de) | 1994-04-06 |
Family
ID=24071694
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91909510A Withdrawn EP0531342A1 (de) | 1990-05-09 | 1991-05-09 | Ringförmige und geradkettige therapeutische peptide |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0531342A1 (de) |
JP (1) | JPH05506862A (de) |
CA (1) | CA2081890A1 (de) |
HU (1) | HUT62604A (de) |
WO (1) | WO1991017181A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6689834B2 (en) | 2000-09-11 | 2004-02-10 | Bayer Aktiengesellschaft | Liquid sulfur-containing oligosiloxanes and their use in rubber mixtures |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6541610B1 (en) * | 1989-09-05 | 2003-04-01 | Immunex Corporation | Fusion proteins comprising tumor necrosis factor receptor |
US5767236A (en) * | 1990-05-09 | 1998-06-16 | Biomeasure, Inc. | Linear therapeutic peptides |
US5834433A (en) * | 1990-07-26 | 1998-11-10 | Merrell Pharmaceuticals Inc. | Compounds and pharmaceutical uses of peptides of bombesin and GRP |
JPH07505865A (ja) * | 1992-02-07 | 1995-06-29 | メレルダウファーマスーティカルズ インコーポレイテッド | ボンベシンのフェニルアラニン類似体類 |
ES2124496T3 (es) * | 1995-03-13 | 1999-02-01 | Biomeasure Inc | Analogos de bombesina. |
US8709998B2 (en) | 2003-04-22 | 2014-04-29 | Ipsen Pharma S.A.S. | Peptide vectors |
KR101642363B1 (ko) | 2008-06-12 | 2016-07-25 | 입센 바이오이노베이션 리미티드 | 신경내분비계 질환의 억제 |
CN102083451A (zh) | 2008-06-12 | 2011-06-01 | 赛恩泰新公司 | 癌症的抑制 |
GB0820970D0 (en) | 2008-11-17 | 2008-12-24 | Syntaxin Ltd | Suppression of cancer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4331661A (en) * | 1980-10-03 | 1982-05-25 | The Salk Institute For Biological Studies | Bombesin analogs |
GB2231051A (en) * | 1989-05-05 | 1990-11-07 | Erba Carlo Spa | Bombesin antagonists |
WO1991004040A1 (en) * | 1989-09-15 | 1991-04-04 | Biomeasure, Inc. | Treatment of colon cancer |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4207311A (en) * | 1977-07-18 | 1980-06-10 | The Salk Institute For Biological Studies | Peptides having analgesic and thermoregulative properties |
GB8427651D0 (en) * | 1984-11-01 | 1984-12-05 | Beecham Group Plc | Compounds |
US4803261A (en) * | 1986-06-27 | 1989-02-07 | The Administrators Of The Tulane Educational Fund | Method for synthesizing a peptide containing a non-peptide |
GB8813356D0 (en) * | 1988-06-06 | 1988-07-13 | Ici Plc | Polypeptide compounds |
-
1991
- 1991-05-09 EP EP91909510A patent/EP0531342A1/de not_active Withdrawn
- 1991-05-09 HU HU9203481A patent/HUT62604A/hu unknown
- 1991-05-09 WO PCT/US1991/003265 patent/WO1991017181A1/en not_active Application Discontinuation
- 1991-05-09 JP JP91509428A patent/JPH05506862A/ja active Pending
- 1991-05-09 CA CA002081890A patent/CA2081890A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4331661A (en) * | 1980-10-03 | 1982-05-25 | The Salk Institute For Biological Studies | Bombesin analogs |
GB2231051A (en) * | 1989-05-05 | 1990-11-07 | Erba Carlo Spa | Bombesin antagonists |
WO1991004040A1 (en) * | 1989-09-15 | 1991-04-04 | Biomeasure, Inc. | Treatment of colon cancer |
Non-Patent Citations (5)
Title |
---|
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. vol. 119, no. 1 , 29 February 1984 , DULUTH, MINNESOTA US pages 14 - 20 N MINAMINO ET AL. 'neuromedin C. a bombesin-like peptide identified in porcine spinal cord' * |
BIOCHEMISTRY. vol. 29, no. 3 , 23 January 1990 , EASTON, PA US pages 616 - 622 L-H WANG ET AL. 'desmethionine alkylamide bombesin analogues: a new class of bombesin receptor antagonists with potent antisecretory activity in pancreatic acini and antimititic activity in Swiss 3T3 cells' * |
BR. J. PHARMACOL. vol. 55 , 1975 , BASINGSTOKE, GB page 221-227 M BROCCARDO ET AL. 'relative potency of bombesin-like peptides' * |
JOURNAL OF BIOLOGICAL CHEMISTRY vol. 265, no. 26 , 15 September 1990 , BALTIMORE, MD US pages 15695 - 15703 L-H WANG ET AL. 'des-met carboxyl-terminally modified analogues of bombesin function as potent bombesin receptor antagonists, partial agonists or agonists' * |
See also references of WO9117181A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6689834B2 (en) | 2000-09-11 | 2004-02-10 | Bayer Aktiengesellschaft | Liquid sulfur-containing oligosiloxanes and their use in rubber mixtures |
Also Published As
Publication number | Publication date |
---|---|
EP0531342A4 (de) | 1994-04-06 |
CA2081890A1 (en) | 1991-11-10 |
JPH05506862A (ja) | 1993-10-07 |
HU9203481D0 (en) | 1993-01-28 |
HUT62604A (en) | 1993-05-28 |
WO1991017181A1 (en) | 1991-11-14 |
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Legal Events
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