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WO1985004872A1 - Analogues peptidiques atriaux - Google Patents

Analogues peptidiques atriaux Download PDF

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Publication number
WO1985004872A1
WO1985004872A1 PCT/US1985/000746 US8500746W WO8504872A1 WO 1985004872 A1 WO1985004872 A1 WO 1985004872A1 US 8500746 W US8500746 W US 8500746W WO 8504872 A1 WO8504872 A1 WO 8504872A1
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Prior art keywords
peptide
gly
ser
desr
accordance
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Jean Edouard Frederic Rivier
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Salk Institute for Biological Studies
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Salk Institute for Biological Studies
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
    • C07K14/582—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • ATRIAL PEPTIDE ANALOGS This invention is directed to peptides related to atrial peptides and to methods for pharmaceutical treatment of mammals using such peptides. More specifically, the invention relates to analogs of atriopeptin I and atriopeptin II, to pharmaceutical compositions containing such analogs and to methods of treatment of mammals using such analogs.
  • Atriopeptins I and II were characterized by M.
  • Atriopeptin I has the formula: bridging bond between the sulfhydryl groups of the two cysteinyl amino acid residues.
  • Atriopeptin II has the same 21 residues plus the residues Phe and Arg at the C-terminal at positions 22 and 23, respectively.
  • Atriopeptins I and II exhibit potent effects on kidney function and regional vascular resistance; they have natriuretic, diuretic and smooth muscle relaxant activities.
  • R 1 is Ser or D-Ser;
  • R 4 is Phe or desR 4 ;
  • R 5 is Gly or desR 5 ;
  • R 6 is Gly or desR 6 ,
  • R 8 is lie, Nle, Nva or Met;
  • R 12 is Gly or D-Ala;
  • R 16 is Gly or desR 16 ;R 17 is Leu or desR 17 ;
  • R 18 is Gly or desR 18 ;
  • R 22 is Phe or desR 22 ;
  • R 23 is Arg, Arg-Tyr or desR 23 ;
  • Q' is S or C H2 ;
  • Q is S or CH 2 and Y is OH or NHR, where R is H or lower alkyl, provided that either a D-isomer residue is present, or Q or Q' is CH 2 , or one or more of the residues in positions 4-6 and 16-18 is deleted.
  • Pharmaceutical compositions in accordance with the invention include such atrial peptide analogs, or nontoxic addition salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier.
  • the invention provides atrial peptide analogs having the following formula:
  • R 1 is Ser or D-Ser
  • R 4 is Phe or desR 4
  • R 5 is
  • Gly or desR 5 R 6 is Gly or desR 6 ; R 8 is Met, Nle, Nva or lie;
  • R 12 is Gly or D-Ala;
  • R 16 is Gly or desR 16 ;
  • R 17 is Leu or desR 17 ;
  • R 18 is Gly or desR 18 ;
  • R 22 is Phe or desR 22 ;
  • R 23 is Arg,
  • Arg-Tyr or desR 23 Q is S or CH 2 ; Q' is S or CH 2 and Y is OH or NHR, where R is H or lower alkyl, provided that either a D-isomer residue is present, or Q or Q' is CH 2 , or one or more of the residues in positions 4-6 and 16-18 is deleted.
  • the preferred atrial peptide analogs include a disulfide bridge between the sulfhydryl groups of Cys residues; however, other analogs having an equivalent cyclizing bond are also biologically potent.
  • not more than one of the residues in positions 4-6 and not more than one of the residues in positions 16-18 is deleted.
  • the preferred peptides can be synthesized by a suitable method, such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution addition.
  • a suitable method such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution addition.
  • the techniques of exclusively solid-state synthesis are set forth in the textbook "Solid-Phase Peptide Synthesis", Stewart & Young, Freeman & Co., San Francisco, 1969 and are exemplified by the disclosure of U.S. Patent No. 4,105,603, issued August 8, 1978 to Vale et al.
  • the fragment condensation method of synthesis is exemplified in U.S. Patent No. 3,972,859 (August 3, 1976).
  • Other available syntheses are exemplified by U.S. Patent No. 3,842,067 (October 15, 1974) and U.S. Patent No.
  • Synthesis by the use of recombinant DNA techniques may also be used when no unnatural residues are present and should be understood to include the suitable employment of a structural gene coding for the desired form of analog.
  • the synthetic peptide may be obtained by transforming a microorganism using an expression vector including a promoter and operator together with such structural gene and causing such transformed microorganism to express the peptide.
  • a non-human animal may also be used to produce the peptide by gene-farming using such a structural gene and the general techniques set forth in U.S. Patent No. 4,276,282 issued June 30, 1981 or using microinjection of embryos as described in WO83/01783 published 26 May 1983 and WO82/04443 published 23 December 1982.
  • the synthetic peptide is then suitably recovered from the animal by extraction from sera or the like.
  • suitable protecting groups which will prevent a chemical reaction from occurring at that site until the group is ultimately removed.
  • protection of an alpha-amino group on an amino acid or a fragment while that entity reacts at the carboxyl group followed by the selective removal of the alpha-amino protecting group to allow subsequent reaction to take place at that location. Accordingly, it is common that, as a step in the synthesis, an intermediate compound is produced which includes each of the amino acid residues located in its desired sequence in the peptide chain with various of these residues linked to the side-chain protecting groups.
  • a-amino protecting groups contemplated by X are those known to be useful in the art in the step-wise synthesis of polypeptides.
  • classes of a-amino protecting groups covered by X are (1) acyl-type protecting groups, such as formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl(Tos), benzensulfonyl, nitrophenylsulfenyl, tritylsulfenyl, o-nitrophenoxyacetyl, chloroacetyl, acetyl, and ⁇ -chlorobutyryl; (2) aromatic urethan-type protecting groups, such as benzyloxycarbonyl (Z) and substituted Z, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl;
  • the preferred a-amino protecting group is BOC.
  • X 2 is a protecting group for the hydroxyl group of Ser and is preferably selected from the class consisting of acetyl(Ac), benzoyl(Bz), tert-butyl, trityl, tetrahydropyranyl, benzyl ether (Bzl) , 2,6-dichlorobenzyl and Z.
  • the most preferred protecting group is Bzl.
  • X 2 can be hydrogen, which means there is no protecting group on the hydroxyl group.
  • X 3 is a protecting group for Cys preferably selected from the class consisting of p-methoxybenzyl (MeOBzl) , p-methylbenzyl, thioethyl, acetamidomethyl, trityl and Bzl. The most preferred protecting group is p-methoxybenzyl.
  • X 3 can also be hydrogen, meaning that there is no protecting group on the sulfur.
  • X 4 is a protecting group for the guanidino group of Arg preferably selected from the class consisting of nitro, Tos, Z, adamantyloxycarbonyl and
  • BOC or is hydrogen. Tos is most preferred.
  • X 5 is hydrogen or an ester-forming protecting group for the ß-carboxyl group of Asp preferably selected from the class consisting of Bzl,
  • X 6 is hydrogen or a protecting group for the amido group of Gin or Asn and is preferably xanthyl (Xan).
  • X 7 is selected from the class consisting of
  • amides, hydrazides and esters including an amide, a benzyl ester or a hydroxymethyl ester anchoring bond used in solid phase synthesis for linking to a solid resin support, represented by the formulae: -NH-benzhydrylamine (BHA) resin support, -NH-paramethylbenzhydrylamine (MBHA) resin support,
  • the polystyrene polymer is preferably a copolymer of styrene with about 0.5 to 2% divinyl benzene as a cross-linking agent, which causes the polystyrene polymer to be completely insoluble in certain organic solvents.
  • At least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 is a protecting group or resin support.
  • the protecting group should be stable to the reagent and under the reaction conditions selected for removing the a-amino protecting group at each step of the synthesis, (b) the protecting group should retain its protecting properties and not be split off under coupling conditions and (c) the side chain protecting group must be removable, upon the completion of the synthesis containing the desired amino acid sequence, under reaction conditions that will not alter the peptide chain.
  • the peptides are preferably prepared using solid phase synthesis, such as that described by Merrifield, J. Am. Chem. Soc, 85, p 2149 (1964), although other equivalent chemical syntheses known in the art can also be used as previously mentioned.
  • Solid-phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected a-amino acid to a suitable resin.
  • a suitable resin can be prepared by attaching a-amino- and guanidino-protected Arg to a chloromethylated resin or to a hydroxymethyl resin.
  • the preparation of the hydroxymethyl resin is described by Bodansky et al., Chem. Ind. (London) 38, 1597-98 (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories,
  • Preferably 50 weight % TFA in methylene chloride is used with 0-5 weight % 1,2 ethane dithiol.
  • the deprotection is carried out at a temperature between about 0°C and room temperature.
  • Other standard cleaving reagents and conditions for removal of specific a-amino protecting groups may be used as described in Schroder & Lubke, "The Peptides", 1 pp 72-75 (Academic Press 1965).
  • the remaining a-amino- and side chain-protected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore.
  • some of them may be coupled to one another prior to addition to the solid phase reactor.
  • the selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as coupling reagents are N,N'-dicyclohexyl carbodiimide (DCCI) and N,N'-diisopropylcarbodiimide(DICI).
  • activating reagents used in the solid phase synthesis of the peptides are well known in the peptide art.
  • suitable activating reagents are: (1) carbodiimides, such as N,N'-diisopropyl carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide; (2) cyanamides such as N,N'-dibenzylcyanamide; (3) keteimines; (4) isoxazolium salts, such as
  • N-ethyl-5-phenyl isoxazolium-3'-sulfonate (5) monocyclic nitrogen-containing heterocyclic amides of aromatic character containing one through four nitrogens in the ring, such as imidazolides, pyrazolides, and 1,2,4-triazolides.
  • heterocyclic amides that are useful include N,N'-carbonyl diimidazole, N,N'-carbonyl-di-1,2,4-triazole; (6) alkoxylated acetylene, such as ethoxyacetylene; (7) reagents which form a mixed anhydride with the carboxyl moiety of the amino acid, such as ethylchloroformate and isobutylchloroformate and (8) nitrogen-containing heterocyclic compounds having a hydroxy group on one ring nitrogen, such as N-hydroxyphthalimide, N-hydroxysuccinimide and 1-hydroxybenzotriazole (HOBT).
  • Other activating reagents and their use in peptide coupling are described by Schroder & Lubke, supra, in Chapter III and by Kapoor, J. Phar. Sci., 59, pp 1-27 (1970).
  • Each protected amino acid or amino acid sequence is introduced into the solid phase reactor in about a two-to fourfold excess, and the coupling is carried out in a medium of dimethylformamide(DMF) :CH 2 Cl 2 (1:1) or in DMF or CH 2 Cl 2 alone.
  • the coupling is carried out manually, the success of the coupling reaction at each stage of the synthesis is monitored by the ninhydrin reaction, as described by E. Kaiser et al., Anal. Biochem. 34, 595 (1970).
  • the coupling procedure is repeated before removal of the a-amino protecting group prior to the coupling of the next amino acid.
  • the coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al., Biopolymers, 1978, 17, pp.1927-1938.
  • the intermediate peptide is removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride, which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups X 2 , X 3 , X 4 , X 5 and X 6 and the a-amino protecting group X 1 , to obtain the peptide in its linear form.
  • a reagent such as liquid hydrogen fluoride
  • the intermediate peptide may be separated from the resin support by alcoholysis after which the recovered C-terminal ester is converted to the acid by hydrolysis. Any side chain protecting groups may then be cleaved as previously described or by other known procedures, such as catalytic reduction (e.g. Pd on BaSO 4 ).
  • catalytic reduction e.g. Pd on BaSO 4
  • anisole and methylethyl sulfide are included in the reaction vessel for scavenging.
  • Example sets forth the preferred method for synthesizing atrial peptide analogs by the solid-phase technique.
  • EXAMPLE I The synthesis of the analog [D-Ala 12 -Phe 22 ] - APN-I having the formula: stepwise manner on a chloromethylated resin, such as LS-601 available from Lab Systems, Inc., containing 0.9 Meq Cl/gm. resin. Coupling of BOC-Phe to the washed resin is performed by the procedure set forth by Horiki et al., in Chemistry Letters (Chem. Soc. of Japan (1978) pp. 165-168, and it results in the substitution of about 0.35 mmol. Phe per gram of resin. All solvents that are used are carefully degassed, preferably by sparging With an inert gas, e.g., helium, to insure the absence of oxygen.
  • an inert gas e.g., helium
  • the coupling reaction is carried out in the reaction vessel of a Beckman Model 990 automatic peptide synthesizer which is programmed to perform the following general work cycle: (a) methylene chloride; (b) 60% trifluoroacetic acid in methylene chloride (2 times for 10 and 15 min resp.); (c) isopropyl alcohol wash; (d) 10% triethylamine in methylene chloride (2 times alternated with methanol wash); and (e) methylene chloride wash.
  • the washed resin (2g.) is stirred with 1.5 mmoles of BOC-Phe in methylene chloride and diisopropylcarbodiimide (1.5 mmoles) was added.
  • BOC-Arg(Tos) or BOC-Asn(Xan) or BOC-Gln(Xan) is being coupled, a mixture of 90% DMF and methylene chloride is used.
  • Bzl is used as the hydroxyl side-chain protecting group for Ser.
  • P-nitrophenyl ester (ONp) can also be used to activate the carboxyl end of Asn, and
  • BOC-Asn(ONp) is coupled overnight using one equivalent of HOBt in a 90% mixture of DMF and methylene chloride. Gin can also be similarly coupled.
  • BOC-Asn and BOC-Gln are coupled using 1 meq. HOBt and 1 meq. DCCI in DMF.
  • Tos is used to protect the guanidino group of Arg, and the aspartic carboxyl group is protected by OBzl.
  • the amido group of Asn is protected by Xan.
  • the resin-peptide is washed with dry diethyl ether, and the peptide is then extracted with de-gassed 2N aqueous acetic acid and separated from the resin by filtration.
  • the cleaved and deprotected peptide is then air-oxidized under high dilution or is added dropwise to a potassium ferricyanide solution to form the disulfide bond between the Cys residues, as described by Rivier et al. in Biopolymers, Volume 17 (1978) pp. 1927-1938.
  • the peptide is chromatographed on both anion- and cation-exchange resins using the methods described in the Rivier et al. article and then lyophilized.
  • the peptide is then purified by gel permeation followed by semi-preparative HPLC as described in Rivier et al., Peptides: Structure and Biological Function (1979) pp. 125-128. The chromatographic fractions are carefully monitored by HPLC, and only the fractions showing substantial purity were pooled. To check whether the precise composition was achieved, the analog is hydrolyzed in sealed evacuated tubes containing 4N methanesulfonic acid and 0.2% tryptamine for 24 hours at 110°C. Amino acid analyses of the hydrolysates using a Beckman 121 MB amino acid analyzer shows that the 22-residue peptide structure is obtained.
  • the peptide [D-Ser 1 , desAA 4,5,6,16,17,18 , is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE III The peptide [D-Ser 1 , Phe 22 ] -APN-I, having is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE IV The peptide [D-Ser 1 ,D-Ala 12 ,Phe 22 ]-APN-I- Ser-Phe-NH 2 is synthesized using the same general procedure as set forth in Example I but employing a MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE V The peptide [D-Ser 1 , desAA 4,5,6,16,17,18 , D Ser-Phe-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [D-Ser 1 , desAA 4,5,6,16,17,18 , OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [D-Ser 1 , desAA 4,5,6,16,17,18 , is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XIV The peptide [Nva 8 ,desAA 4,5,6,16,17,18 ] 0 is synthesized as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE XV
  • EXAMPLE XVII The peptide [D-Ser 1 , desAA 4,5,6,16,r7,18 ]- - using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XVIII The peptide [D-Ser 1 ]-APN-I, having the synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XXI The peptidde [desAA 4,5,6,16,17,18 ]- synthesized as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XXII The peptide [dicarba 3,19 ]-APN-I, having the - synthesized using the same general procedure as set forth in Example I; however the cyclizing technique set forth in U.S. Patent No. 4,161,521 is employed to provide the linkage between the moieties which occupy positions-3 and 19 in the ultimate peptide. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XXIV The peptide [D-Ala 12 , dicarba 3,19 ]-APN-I- NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing an MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XXV The peptide [desAA 4,5,6,16,17,18 , Met 8 , D-Ala 12 , dicarba 3,19 ]-APN-I is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • Nle 8 , D-Ala 12 , dicarba 3,19 ]-APN-II is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [D-Ala 12 , dicarba 3,19 ]-APN-II- NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing a MBHA resin.
  • the peptide [D-Ser 1 , dicarba 3,19 ]-APN-II is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [dicarba 3,19 , Phe 22 ]-APN-I-NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing a MBHA resin.
  • Phe 22 ]-APN-I-NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing a MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XXXV The peptide [D-Ser 1 , desAA 4,5,6,16,17,18 , D- Ser-NHCH 3 is synthesized using the same general procedure as set forth in Example I but employing an N-methylbenzhydrylamine resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XXXIX The peptide [desAA 4,5,6,16,17,18 , dicarba 3,19 , D-Ala 12 , Phe 22 ] -APN-I is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XL The peptide [D-Ser 1 , dicarba 3,19 ,
  • Phe 22 ]-APN-I is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • Phe-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • Phe-OH is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • Phe-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE XLIV The peptide [D-Ser 1 ,D-Ala 12 ,desGly 5 , Phe 22 ]- Ser-Phe-NH 2 is synthesized using the same general procedure as set forth in Example I but employing a MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE XLV
  • the peptide [D-Ser 1 , desAA 5,18 ,D-Ala 12 , -Asn-Ser-Phe-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • Phe-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [D-Ser 1 , desAA 4,18 , D-Ala 12 , Cys-Asn-Ser-Phe-Arg-Tyr-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE IL The peptide [D-Ser 1 , Tyr 24 ]-APN-II-NH 2 Asn-Ser-Phe-Arg-Tyr-NH 2 is synthesized as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE L
  • the peptide [D-Ser 1 , desAA 4,5,17,18 , Phe-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LI The peptide [D-Ser 1 ,D-Ala 12 ,Tyr 24 ]-APN-II-NH 2 is synthesized using the same general procedure as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LII The peptide [dicarba 3,19 , desGly 16 ,Phe 22 ]-APN-I-NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing a MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [dicarba 3,19 , Met 8 , D-Ala 12 , desGly 16 ,Phe 22 ]-APN-I-NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing a MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LVIII The peptide [D-Ser 1 ,Met 8 ,desGly 18 ]-APN-I-NHCH 3 , NHCH 3 is synthesized using the same general procedure as set forth in Example XXXV. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [desAA 5,16, dicarba 3,19 , D-Ala 12 , Phe 22 ]-APN-I is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LX The peptide [D-Ser 1 , desAA 5,17, Met 8 ]- APN-II, having the formula: H-D-Ser-Ser-Cys-Phe-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Gly-Cys-Asn-Ser-Phe-Arg-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE LXI
  • the peptide [D-Ser 1 ,desGly 5 ]-APN-II-NH 2 , Arg-NH 2 is synthesized as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LXII The peptide [desAA 5,18 , D-Ala 12 ]-APN-II, is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE LXIII
  • EXAMPLE LXIV The peptide [Nva 8 ,desAA 5,16 ]-APN-II-NH 2 , is synthesized as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE LXV
  • the peptide [D-Ser 1 , desAA 5,17, D-Ala 12 ]-APN-I having the formula: H-D-Ser-Ser-Cys-Phe-Gly-Arg-Ile-Asp- Arg-Ile-D-Ala-Ala-Gln-Ser-Gly-Gly-Cys-Asn-Ser-OH is synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained. EXAMPLE LXVI
  • EXAMPLE LXVII The peptide [D-Ser 1 , desAA 4,18 ]-APN-I, - g y y y synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LXVIII The peptide [D-Ser 1 , desAA 4,18 ]-APN-I, - g y y y synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LXVIII The peptide [D-Ser 1 , desAA 4,18 ]-APN-I, - g y y y synthesized using the same general procedure as set forth in Example I. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LXVIII The peptide [D-Ser 1 , desAA 4,18 ]-APN
  • the peptide [D-Ser 1 , desGly 16 ]-APN-I-NH 2 is synthesized using the same general procedure as set forth in Example IV. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [desGly 5 ,D-Ala 12 , dicarba 3,19 ]-APN-I- NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing an MBHA resin.
  • the peptide [desAA 4,18 , D-Ala 12 , dicarba 3,19 ] - APN-I is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • APN-II is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LXXVII The peptide [dicarba 3,19 ,desGly 18 ]-APN-II-NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing an MBHA resin. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [desAA 4,16 ' Met 8 , dicarba 3,19 ]-APN-II is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • the peptide [desAA 4,18 , Nle 8 , D-Ala 12 , dicarba 3,19 ]-APN-II is synthesized using the same general procedure as set forth in Example XXII. Amino acid analysis shows that the desired peptide structure is obtained.
  • EXAMPLE LXXX The peptide [desGly 5 ,D-Ala 12 , dicarba 3,19 ]-APN-II- NH 2 is synthesized using the same general procedure as set forth in Example XXII but employing a MBHA resin.
  • Amino acid analysis shows that the desired peptide structure is obtained.
  • In vivo testing of analogs of APN-I and APN-II shows that all of the peptides synthesized in the foregoing Examples exhibit natriuretic and diuretic activity. The testing is done using anesthetized Sprague-Dawley rats using the procedure as set forth in detail in an article by M.G. Currie, P.N.A.S. U.S.A.
  • APN-II analogs of APN-II are more potent than the comparable analogs of APN-I, and the iv administration of one microgram or less of the APN-II analogs induces an increase in urinary sodium excretion of 10 times or more.
  • natriuretic and diuretic activity may be used to relieve hypertension or to counteract congestive heart failure by effecting a lowering of blood pressure.
  • administration of these analogs or the non-toxic addition salts thereof, combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition may be made to mammals, including humans, either intravenously, subcutaneously, intramuscularly, intranasally or orally, and a dosage of between about 1 rnicrogram to about 10 milligrams per kilogram of body weight may be employed to take advantage of the natriuretic and diuretic activity.
  • the peptides may be employed for diagnostic purposes and/or in connection with surgery to serve as intestinal and/or vascular smooth muscle relaxants under the guidance of a physician who will be able to determine appropriate dosages from available test information and the case history of the patient in question.
  • Such peptides are often administered in the form of pharmaceutically acceptable nontoxic salts, such as acid addition salts or metal complexes, e.g., with zinc, iron, calcium, barium, magnesium, aluminum or the like (which are considered as addition salts for purposes of this application).
  • acid addition salts are hydrochloride, hydrobromide, sulphate, phosphate, tannate, pamoate, oxalate, fumarate, gluconate, alginate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate and the like.
  • the tablet may contain a binder, such as tragacanth, corn starch or gelatin; a disintegrating agent, such as alginic acid; and a lubricant, such as magnesium stearate.
  • a binder such as tragacanth, corn starch or gelatin
  • a disintegrating agent such as alginic acid
  • a lubricant such as magnesium stearate.
  • sweetening and/or flavoring may be used, and intravenous administration in isotonic saline, phosphate buffer solutions or the like may be effected.
  • the peptides should be administered under the guidance of a physician, and pharmaceutical compositions will usually contain the peptide in conjunction with a conventional, pharmaceutically-acceptable carrier. Usually, the dosage will be from about 2 to about 200 micrograms of the peptide per kilogram of the body weight of the host when the peptide is being used for other than its diuretic activity.

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Abstract

Analogues peptidiques atriaux de formule (I) où R1 représente Ser ou D-Ser; R4 représente Phe ou desR4; R5 représente Gly ou desR5; R6 représente Gly ou desR6; R8 représente Met, Nle, Nva ou Ile; R12 représente Gly ou D-Ala; R16 représente Gly ou desR16; R17 représente Leu ou desR17; R18 représente GLy ou desR18; R22 représente Phe ou desR22; R23 représente Arg, Arg-Tyr ou desR23; Q représente S ou CH2; Q' représente S ou CH2 et Y représente OH ou NHR, où R représente H ou un alkyl inférieur. Soit un résidu D-isomère est présent, soit Q ou Q' représente CH2, soit un ou plusieurs des résidus en position 4-6 et 16-18 sont effacés. Ces analogues ou leurs sels pharmaceutiquement acceptables, dispersés dans un liquide pharmaceutiquement acceptable ou un porteur solide, peuvent être administrés aux mammifères pour leur activité natriurétique et diurétique, pour soulager l'hypertension ou pour contrecarrer un arrêt du coeur congestif.
PCT/US1985/000746 1984-04-24 1985-04-22 Analogues peptidiques atriaux Ceased WO1985004872A1 (fr)

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0173557A3 (en) * 1984-08-29 1987-07-15 Ajinomoto Co., Inc. Peptides
EP0147193A3 (en) * 1983-12-26 1987-08-12 Suntory Limited Peptide production and use thereof
WO1988003537A1 (fr) * 1986-11-07 1988-05-19 Novo Industri A/S Nouveaux peptides
WO1988005306A1 (fr) * 1987-01-23 1988-07-28 The General Hospital Corporation Atriopeptines, activateurs de guanylate cyclase, et inhibiteurs de phosphodiesterase utilises pour traiter le glaucome, l'hydrocephalie et l'oedeme cerebral (troubles volumiques du liquide cephalo-rachidien)
US4891358A (en) * 1987-12-16 1990-01-02 Bio-Mega Inc. ANE derivatives with novel bridging
WO1990000561A1 (fr) * 1988-07-07 1990-01-25 Novo Nordisk A/S Nouveaux peptides
EP0232078A3 (fr) * 1986-01-31 1990-03-14 Merck & Co. Inc. Peptides à activité "ANF"
EP0266170A3 (fr) * 1986-10-28 1990-04-11 Takeda Chemical Industries, Ltd. Dérivé d'un peptide, et sa production
US5057603A (en) * 1986-01-31 1991-10-15 Merck & Co., Inc. Peptides having ANF activity
EP0418308A4 (en) * 1988-05-31 1991-11-13 California Biotechnology, Inc. Recombinant techniques for production of novel natriuretic and vasodilator peptides
US5095004A (en) * 1987-03-25 1992-03-10 Bio-Mega Inc. Fluorine containing atrial natriuretic peptides
DE4032269A1 (de) * 1990-10-11 1992-04-16 Boehringer Ingelheim Kg Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE4032271A1 (de) * 1990-10-11 1992-04-16 Boehringer Ingelheim Kg Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE4032268A1 (de) * 1990-10-11 1992-04-16 Boehringer Ingelheim Kg Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US5500230A (en) * 1987-01-23 1996-03-19 The General Hospital Corporation Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators
US5665704A (en) * 1993-11-12 1997-09-09 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5846932A (en) * 1993-11-12 1998-12-08 Genentech, Inc. Receptor specific atrial natriuretic peptides
US6525022B1 (en) 1993-11-12 2003-02-25 Genentech, Inc. Receptor specific atrial natriuretic peptides
US7211380B1 (en) 1989-03-01 2007-05-01 Shionogi & Co., Ltd. Physiologically active polypeptide and DNA
WO2007115175A2 (fr) 2006-03-30 2007-10-11 Palatin Technologies, Inc. Constructions de peptides natriurétiques cycliques
US7795221B2 (en) 2006-03-30 2010-09-14 Palatin Technologies, Inc. Linear natriuretic peptide constructs
US8580746B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Amide linkage cyclic natriuretic peptide constructs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4508712A (en) * 1984-01-10 1985-04-02 Washington University Atrial peptide

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US4496544A (en) * 1983-11-10 1985-01-29 Washington University Atrial Peptides
US4508712A (en) * 1984-01-10 1985-04-02 Washington University Atrial peptide

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US4496544A (en) * 1983-11-10 1985-01-29 Washington University Atrial Peptides
US4508712A (en) * 1984-01-10 1985-04-02 Washington University Atrial peptide

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Biochemical and Biophysical Research Communication, Vol. 118, issued 1984, pages 131-139 KANGAWA, et al. *
Biochemical and Biophysical Research Communications, Vol. 117, issued 1983, pages 859-865 FLYNN, et al *
Biochemical and Biophysical Research Communications, Vol. 119, issued 1984, pages 524-529 MISONO, et al. *
CHEMICAL ABSTRACT, Vol. 94, issued 1981, page 62919, DE BOLD, et al. *
CHEMICAL ABSTRACT, Vol. 97, issued 1982, page 175913 TRIPPODO, et al. *
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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0147193A3 (en) * 1983-12-26 1987-08-12 Suntory Limited Peptide production and use thereof
EP0173557A3 (en) * 1984-08-29 1987-07-15 Ajinomoto Co., Inc. Peptides
EP0232078A3 (fr) * 1986-01-31 1990-03-14 Merck & Co. Inc. Peptides à activité "ANF"
US5057603A (en) * 1986-01-31 1991-10-15 Merck & Co., Inc. Peptides having ANF activity
EP0266170A3 (fr) * 1986-10-28 1990-04-11 Takeda Chemical Industries, Ltd. Dérivé d'un peptide, et sa production
WO1988003537A1 (fr) * 1986-11-07 1988-05-19 Novo Industri A/S Nouveaux peptides
WO1988005306A1 (fr) * 1987-01-23 1988-07-28 The General Hospital Corporation Atriopeptines, activateurs de guanylate cyclase, et inhibiteurs de phosphodiesterase utilises pour traiter le glaucome, l'hydrocephalie et l'oedeme cerebral (troubles volumiques du liquide cephalo-rachidien)
US5500230A (en) * 1987-01-23 1996-03-19 The General Hospital Corporation Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators
US5095004A (en) * 1987-03-25 1992-03-10 Bio-Mega Inc. Fluorine containing atrial natriuretic peptides
EP0320967B1 (fr) * 1987-12-16 1993-12-08 Bio-Mega/Boehringer Ingelheim Research Inc. Dérivés d'ANF avec un pont modifié
US4891358A (en) * 1987-12-16 1990-01-02 Bio-Mega Inc. ANE derivatives with novel bridging
US5948761A (en) * 1988-05-31 1999-09-07 Scios, Inc. Recombinant canine brain natriuretic peptide
EP0418308A4 (en) * 1988-05-31 1991-11-13 California Biotechnology, Inc. Recombinant techniques for production of novel natriuretic and vasodilator peptides
US7179790B2 (en) 1988-05-31 2007-02-20 Scios, Inc. Brain natriuretic peptide
US6974861B2 (en) 1988-05-31 2005-12-13 Scios, Inc. Pharmaceutical compositions and methods using natriuretic peptides
US6897030B2 (en) 1988-05-31 2005-05-24 Scios, Inc. Immunoassays for human brain natriuretic peptide
US5674710A (en) * 1988-05-31 1997-10-07 Scios, Inc. Recombinant techniques for production of human brain natriuretic peptide
US6586396B1 (en) 1988-05-31 2003-07-01 Scios, Inc. Subcutaneous administration of natriuretic peptide
WO1990000561A1 (fr) * 1988-07-07 1990-01-25 Novo Nordisk A/S Nouveaux peptides
US7211380B1 (en) 1989-03-01 2007-05-01 Shionogi & Co., Ltd. Physiologically active polypeptide and DNA
DE4032268A1 (de) * 1990-10-11 1992-04-16 Boehringer Ingelheim Kg Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE4032271A1 (de) * 1990-10-11 1992-04-16 Boehringer Ingelheim Kg Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE4032269A1 (de) * 1990-10-11 1992-04-16 Boehringer Ingelheim Kg Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US6525022B1 (en) 1993-11-12 2003-02-25 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5846932A (en) * 1993-11-12 1998-12-08 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5665704A (en) * 1993-11-12 1997-09-09 Genentech, Inc. Receptor specific atrial natriuretic peptides
WO2007115175A2 (fr) 2006-03-30 2007-10-11 Palatin Technologies, Inc. Constructions de peptides natriurétiques cycliques
US7622440B2 (en) 2006-03-30 2009-11-24 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US7795221B2 (en) 2006-03-30 2010-09-14 Palatin Technologies, Inc. Linear natriuretic peptide constructs
US8580747B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US8580746B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Amide linkage cyclic natriuretic peptide constructs

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AU4292785A (en) 1985-11-15
EP0177610A1 (fr) 1986-04-16

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