WO1991017181A1 - Peptides therapeutiques lineaires et cyclises - Google Patents

Peptides therapeutiques lineaires et cyclises Download PDF

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Publication number
WO1991017181A1
WO1991017181A1 PCT/US1991/003265 US9103265W WO9117181A1 WO 1991017181 A1 WO1991017181 A1 WO 1991017181A1 US 9103265 W US9103265 W US 9103265W WO 9117181 A1 WO9117181 A1 WO 9117181A1
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WO
WIPO (PCT)
Prior art keywords
ala
leu
phe
trp
val
Prior art date
Application number
PCT/US1991/003265
Other languages
English (en)
Inventor
David H. Coy
Sun Hyuk Kim
Jacques-Pierre Moreau
Original Assignee
The Administrators Of The Tulane Educational Fund
Biomeasure, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The Administrators Of The Tulane Educational Fund, Biomeasure, Inc. filed Critical The Administrators Of The Tulane Educational Fund
Priority to JP91509428A priority Critical patent/JPH05506862A/ja
Publication of WO1991017181A1 publication Critical patent/WO1991017181A1/fr
Priority to NO92924293A priority patent/NO924293L/no
Priority to FI925055A priority patent/FI925055A0/fi

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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
    • C07K7/08—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.

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  • 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)

Abstract

Peptide thérapeutique comprenant entre sept et dix restes d'acides aminés. De plus, le peptide est un analogue des peptides suivants qui se produisent naturellement et se terminent à la terminaison carboxy avec un reste Met: (a) litorine; (b) la région de GRP mammifère à terminaison carboxy de dix acides aminés, neuromédine B, ou neuromédine C; et (c) la région de bombésine amphibie à terminaison carboxy de dix acides aminés, l'analogue susmentionné étant un antagoniste d'un des peptides qui se produisent naturellement.
PCT/US1991/003265 1990-05-09 1991-05-09 Peptides therapeutiques lineaires et cyclises WO1991017181A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP91509428A JPH05506862A (ja) 1990-05-09 1991-05-09 環状および鎖状の治療用ペプチド
NO92924293A NO924293L (no) 1990-05-09 1992-11-06 Cykliserte og lineaere terapeutiske peptider
FI925055A FI925055A0 (fi) 1990-05-09 1992-11-06 Cykliska och lineaera terapeutiska peptider

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52022690A 1990-05-09 1990-05-09
US520,226 1990-05-09

Publications (1)

Publication Number Publication Date
WO1991017181A1 true WO1991017181A1 (fr) 1991-11-14

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ID=24071694

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Application Number Title Priority Date Filing Date
PCT/US1991/003265 WO1991017181A1 (fr) 1990-05-09 1991-05-09 Peptides therapeutiques lineaires et cyclises

Country Status (5)

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EP (1) EP0531342A1 (fr)
JP (1) JPH05506862A (fr)
CA (1) CA2081890A1 (fr)
HU (1) HUT62604A (fr)
WO (1) WO1991017181A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5428018A (en) * 1992-02-07 1995-06-27 Merrell Dow Pharmaceuticals Inc. Phenylalanine analogs of bombesin
EP0737691A1 (fr) * 1995-03-13 1996-10-16 Biomeasure, Inc. Analogues de bombésine
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
US6541610B1 (en) * 1989-09-05 2003-04-01 Immunex Corporation Fusion proteins comprising tumor necrosis factor receptor
EP2161037A2 (fr) 2003-04-22 2010-03-10 Ipsen Pharma Conjugués de Camptothecin-Somatostatin
EP2664343A2 (fr) 2008-11-17 2013-11-20 Syntaxin Limited Suppression du cancer
EP3473643A1 (fr) 2008-06-12 2019-04-24 Ipsen Bioinnovation Limited Protéines de fusion pour leur utilisation dans le traitement du cancer
EP3590956A1 (fr) 2008-06-12 2020-01-08 Ipsen Bioinnovation Limited Suppression de maladies neuroendocrines

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10044989A1 (de) 2000-09-11 2002-03-21 Bayer Ag Flüssige schwefelhaltige Oligosiloxane und ihre Verwendung in Kautschukmischungen

Citations (4)

* Cited by examiner, † Cited by third party
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
US4737487A (en) * 1984-11-01 1988-04-12 Beecham Group P.L.C. VIP type peptides
US4803261A (en) * 1986-06-27 1989-02-07 The Administrators Of The Tulane Educational Fund Method for synthesizing a peptide containing a non-peptide
EP0345990A2 (fr) * 1988-06-06 1989-12-13 Zeneca Limited Composés polypeptide

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4331661A (en) * 1980-10-03 1982-05-25 The Salk Institute For Biological Studies Bombesin analogs
GB2231051B (en) * 1989-05-05 1992-12-16 Erba Carlo Spa Bombesin antagonists
EP0448677A4 (en) * 1989-09-15 1992-08-26 Biomeasure Inc. Treatment of colon cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
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
US4737487A (en) * 1984-11-01 1988-04-12 Beecham Group P.L.C. VIP type peptides
US4803261A (en) * 1986-06-27 1989-02-07 The Administrators Of The Tulane Educational Fund Method for synthesizing a peptide containing a non-peptide
EP0345990A2 (fr) * 1988-06-06 1989-12-13 Zeneca Limited Composés polypeptide

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Biochemistry, Volume 17, No. 9, issued 1978, RIVIER et al., "Bombesin, Bombesin Analogues, and related peptides: Effects on Thermoregulation", pages 1766-1771. See Table I in particular. *
LEHNINGER, "Principles of Biochemistry", published 1982 by Worth Publisher, Inc., pages 95-117. See Table 5-3 in particular. *
Proc. Natl. Acad. Sci. US, Volume 82, issued November 1985, ZACHARY et al., "High-affinity receptors for peptides of the bombesin family in Swiss 3T3 cells", pages 7616-7620. See Table 2 in particular. *
See also references of EP0531342A4 *
The Journal of Biological Chemistry, Volume 262, No. 34, issued 05 December 1987, HEIKKILA et al., "Bombesin-related peptides Induce Calcium Mobilization in a subset of Human Small Cell Lung Cancer Cell Lines", pages 16456-16460. See Figure 5 in particular. *

Cited By (11)

* Cited by examiner, † Cited by third party
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
US5428018A (en) * 1992-02-07 1995-06-27 Merrell Dow Pharmaceuticals Inc. Phenylalanine analogs of bombesin
EP0737691A1 (fr) * 1995-03-13 1996-10-16 Biomeasure, Inc. Analogues de bombésine
EP2161037A2 (fr) 2003-04-22 2010-03-10 Ipsen Pharma Conjugués de Camptothecin-Somatostatin
EP2662087A1 (fr) 2003-04-22 2013-11-13 Ipsen Pharma Vecteurs de somatostatine
EP3473643A1 (fr) 2008-06-12 2019-04-24 Ipsen Bioinnovation Limited Protéines de fusion pour leur utilisation dans le traitement du cancer
EP3590956A1 (fr) 2008-06-12 2020-01-08 Ipsen Bioinnovation Limited Suppression de maladies neuroendocrines
EP2664343A2 (fr) 2008-11-17 2013-11-20 Syntaxin Limited Suppression du cancer
EP3241560A1 (fr) 2008-11-17 2017-11-08 Ipsen Bioinnovation Limited Suppression du cancer

Also Published As

Publication number Publication date
HUT62604A (en) 1993-05-28
CA2081890A1 (fr) 1991-11-10
HU9203481D0 (en) 1993-01-28
EP0531342A1 (fr) 1993-03-17
JPH05506862A (ja) 1993-10-07
EP0531342A4 (fr) 1994-04-06

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