WO1994003494A1 - Agents mimetiques restreints dans leur conformation de girations inverses, et peptides les contenant - Google Patents

Agents mimetiques restreints dans leur conformation de girations inverses, et peptides les contenant Download PDF

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WO1994003494A1
WO1994003494A1 PCT/US1993/007447 US9307447W WO9403494A1 WO 1994003494 A1 WO1994003494 A1 WO 1994003494A1 US 9307447 W US9307447 W US 9307447W WO 9403494 A1 WO9403494 A1 WO 9403494A1
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bound
support
mimetic
beta
turn
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PCT/US1993/007447
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Michael Kahn
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The Board Of Trustees Of The University Of Illinois
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Priority to AU50006/93A priority Critical patent/AU679460B2/en
Priority to EP93919936A priority patent/EP0656907A1/fr
Priority to JP6505602A priority patent/JPH07509723A/ja
Publication of WO1994003494A1 publication Critical patent/WO1994003494A1/fr
Priority to KR1019950700471A priority patent/KR950703000A/ko

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70514—CD4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to peptide mimetics.
  • Peptide mimetics are compositionally well defined, configurationally constrained chemical structures which can serve as surrogates for peptides or proteins in their interactions with receptors, antibodies, and/or enzymes.
  • This invention also relates to a means for three dimensional analysis of specific interactions between peptides and proteins and the complementary regions on receptors, antibodies and enzymes, as well as the development of new therapeutic agents through the use of peptide mimetics.
  • Peptides and proteins play critical roles in the regulation of all biological processes. Peptides, for example, play a regulatory role as hormones and inhibitors, and are also involved in immunological recognition. The significant biological role of peptides makes important the understanding of the interactions between peptides and their receptors or enzymes to which they bind.
  • peptide mimetics can be defined as structures which serve as appropriate substitutes for peptides in interactions with receptors and enzymes.
  • the development of rational approaches for discovering peptide mimetics is a major goal of medicinal chemistry. Such development has been attempted both by empirical screening approaches and by specific synthetic design.
  • Chipkin et al. Ann. Rep. Med. Chem. 23.: 11 (1988), discloses discovery of ligands for the u-opioid receptor by this approach; as does Romar et al. ,
  • peptides containing conformationally constrained mimetics of beta- urns are particularly desirable. Such peptides have been produced using either external or internal beta- urn mimetics.
  • bicyclic lactams reduces problems of flexibility somewhat, conformational analysis of peptides containing these mimetics may still be -desirable. Moreover, the side chain hindrance in these molecules may be even worse than that in the monocyclic lactams. Finally, both monocyclic and bicyclic lactams mimic only type II and type II' beta-turns, whereas type I and type III beta-turns are more prevalent in proteins and presumably in peptides.
  • the limitations presented by external beta ⁇ urn mimetics may be minimized by using mimetics in which the mimetic skeleton approximately replaces the space that was occupied by the peptide backbone in the natural beta- urn. Such molecules are known as internal beta-turn mimetics. Internal beta-turn mimetics may not generally reproduce the geometry of the peptide backbone of the particular beta-turn as accurately as external beta-turn mimetics. However, the internal position of the constraint allows replacement of larger sections of peptide, thus making tetrapeptide mimetics possible. The lack of bulk also diminishes the likelihood of steric hindrance of the side chains by the mimetic skeleton.
  • Tetrahedron Lett.2 .' 4841-4844 (1986) discloses an internal beta-turn mimetic, based upon an indolizidinone skeleton, and designed to mimic the lysine and arginine side-chain disposition of the immunosuppressing tripeptide Lys-Pro-Arg.
  • Kahn et al. Heterocycles 2£: 29-31 (1987), discloses an internal beta-turn mimetic, based upon an indolizidinone skeleton, and designed to correctly position the aspartyl and arginyl side chains of a beta-turn in the proposed bioactive region of erabutoxi .
  • Arrhenius et al. 11th Proc. Am. Peptide Symp., Rivier and Marshall, Eds., Escom, Leiden (1990), discloses substitution of an amide-amide backbone hydrogen bond with a covalent hydrogen bond mimic to produce an alpha-helix mimetic.
  • the invention provides materials and methods for the synthesis of reverse turn mimetics. More particularly, the invention provides a modular system for synthesizing reverse turn mimetics having nearly infinite variability in degree of conformational constraint, flexibility, side chain constituents, and in the size and bond angles of the mimetic skeleton.
  • the invention provides modular component pieces for the assembly of reverse turn mimetics.
  • the invention provides solid phase synthesis and liquid phase methods for making reverse turn mimetics and for making peptides containing the same.
  • the invention provides novel reverse turn mimetics and novel peptide structures containing such reverse turn mimetics.
  • the invention provides novel synthetic nonpeptide diagnostic, prophylactic, and therapeutic molecules.
  • this invention provides novel methods for determining receptor structure and for identifying agonists and antagonists thereto.
  • the materials and methods of the invention are useful for probing the molecular interactions between ligands and receptors, antibodies and antigens, enzymes and substrates, and thus for providing therapeutic agonists and antagonists capable of interacting with receptors, antibodies, or enzymes. Additional preferred embodiments of the invention will be made apparent by the following detailed description, examples, and claims.
  • Figures 1 and IA show routes for synthesizing either a reverse turn mimetic according to the invention, or a novel peptide containing the same.
  • the synthesis route shown in Figure 1 utilizes the modular component pieces of the invention in a standard
  • Figure 2 shows preferred embodiments of the linker moiety, X, of the first modular component piece. For each linker shown, n - 0-
  • Aromatic linkers are shown in para configuration, but may alternatively be in ortho or meta configuration.
  • Figure 3 is a synthetic scheme for a reverse turn mimetic of this invention.
  • Figure 4 summarizes data showing inhibition of gpl20 binding by soluble CD4 and by a reverse turn mimetic of the invention.
  • Figure 5 is a reverse turn mimetic of the full CD4 loop region mimetic structure.
  • Figure 6 is a summary of testing of the inhibition of syncytium formation by the mimetic of Figure 5 (asterisks) , soluble CD4 (squares), or CD4 hexapeptide of residues 40-45 (crosses).
  • the invention provides a modular system for producing reverse turn mimetics having a virtually limitless range of skeletal sizes and bond angles, and side chain substituents. Reverse turn mimetics according to the invention can thus have alternative side chain substituents without having any changes in the backbone conformation.
  • reverse turn mimetics according to the invention possess appropriate termini for incorporation into peptides by standard peptide synthesis procedures.
  • the invention provides a system for producing a virtually unlimited array of peptides having reverse turn mimetics according to the invention incorporated therein.
  • the term "reverse term mimetics” is used in a generic sense, and is intended to encompass mimetics of beta turns, gamma turns, beta hairpins, and beta bulges, all of which are provided by the invention by varying the modular component pieces used.
  • the invention provides modular component pieces for the construction of reverse term mimetics.
  • Modular component pieces according to the invention include both L- and D- enantio eric forms.
  • a first modular component piece according to the invention is characterized by the structural formula 11.
  • R* may be any naturally-occurring amino acid side chain subs ituent, or analog thereof, wherein P is a protective group suitable for use in peptide synthesis, wherein R is and wherein the linker moiety, X comprises a linker terminating in an amino or hydrazino group, and wherein the termini of the linker are separated by zero to four carbon atoms, and where the carbon atoms involved in carbon-carbon or carbon-nitro en bonds may be saturated, unsaturated, or aromatic. Specific preferred examples of such linkers are shown in Figure 2.
  • the linker group X may be varied in size and or flexibility to control the conformation of the ring in the final mimetic.
  • Ligands having maximum biological activity can then be subjected to spectroscopic and computer-assisted molecular modeling to infer the bound conformation from the determined solution structure.
  • Such first component piece may be synthesized according to alternative routes, depending on the nature of the X groups.
  • a first route as shown in Example 1, the component is synthesized by the SN2 displacement of an alpha-triflyloxy ester which is readily produced from the corresponding amino acid according to a procedure described by Hoffman and Kim, Tetrahedron Lett. 11: 2953 (1990) or by the direct amination method of Vidal, JCS Chem. Comm. 435 (1991).
  • An alternative route for the synthesis of the first component piece utilizes a quite facile reductive amination reaction, as described by Gribble and Nutaitis, Org. Prep. Proced. Int.
  • a second modular component piece according to the invention comprises an N-protected naturally occurring alpha amino acid or analog thereof which are commercially available or which may be readily synthesized by standard organic synthesis techniques.
  • The- second modular component is represented by the structural formula:
  • a completed mimetic may contain none, one, or two second modular component pieces. When two second modular component pieces are present in a mimetic, the additional R group will be represented in structural formulae as R 3 ' .
  • a third modular component piece according to the invention is characterized by the structural formula:
  • P is a protective group suitable for use in peptide synthesis, wherein Z - H or CH 3 , and wherein R 1 and R 2 are naturally- occurring amino acid side chains or analogs thereof and where I is or iniiH.
  • a preferred protective group is a tert-butyl dimethylsilyl group.
  • Such a third modular component piece according to the invention may be synthesized by the route shown in Examples 6-8, which entails selective generation of the ester enolate and condensation with an appropriate N-silylimine, followed by mild hydrolysis. See Hart and Hu, Chem. Rev. ,89: 1447. Alternative routes to these third component pieces are outlined in: Salzman et al., J. Am. Chem. Soc. 102: 6161 (1980) and; Miller et al., J. Am. Chem. Soc. 102: 7026 (1980); Williams et al. , J. Amer. Chem. Soc. Ill: 1073 (1989). As indicated above, the third modular component piece may be selected from stereoisomers of the same components.
  • stereoisomers of third modular component pieces into the reverse turn mimetics of this invention allows for the synthesis of compounds in a controlled manner, that vary subtly in the orientation of the four R groups; R lf R 2) R 3 and R 4 . This provides for access to essentially all potential turn types and allows for detailed mapping of receptor-bound structures.
  • the invention provides a method for producing beta-turn mimetics, comprising generally the steps shown in Figure 1.
  • the synthesis method used may be liquid synthesis or solid phase synthesis. It is preferred, however, that solid phase synthesis be used to take advantage of the ease of purification and rapid production. In order to maximize the benefits of solid phase peptide synthesis it is beneficial to take advantage of the high yields that can be obtained from the silicon mediated acid fluoride coupling of the first modular component piece with the second modular component piece.
  • a free amino group coupled to a solid support will be the starting point of the solid phase synthesis.
  • the amino group may be coupled to the solid support via a nonpeptide chemical constituent, or it may be the free amino terminus of a nascent peptide being synthesized from the solid support.
  • a first modular component piece according to the invention is then coupled via an amide linkage to the free amino group bound to the solid support, to yield a support- bound first modular component piece.
  • a second modular component piece according to the invention is then coupled to the support-bound first modular component piece using silicon mediated acid fluoride coupling to yield a support- bound nascent beta-turn mimetic.
  • silicon mediated acid fluoride coupling produces a suppor -bound intermediate product in excellent yield, with minimal racemization and with a reasonable rate of reaction.
  • the silicon mediated acid fluoride coupling of a peptide containing an acid fluoride site with a peptide containing a N- silylated bound species results in the formation of a strongly covalent silicon fluoride species by-product allowing the free peptide components to couple.
  • the coupling occurs more efficiently under solid phase synthesis conditions resulting in a high yield of the support-bound nascent reverse turn mimetic.
  • a mixed anhydride coupling or other type of coupling such as for example, BOP or anhydride coupling is then carried out between a third modular component piece and the support-bound nascent beta- turn mimetic to yield a support-bound pre-cyclization beta-turn mimetic.
  • the support-bound pre-cyclization beta-turn mimetic is then cyclized to form a support-bound beta-turn mimetic.
  • peptide synthesis may be continued by adding additional second modular component pieces to the amino acid terminals, or the n
  • support-bound structure may be cleaved from the support, or the mimetic can be screened on the resin.
  • Synthesis of beta-turn mimetics may also be carried out in solution. Synthesis in solution requires essentially the same steps as solid-phase synthesis except that the first modular component piece is not attached to a solid support.
  • Example 15 describes a liquid phase synthesis of a beta- urn mimetic of this invention.
  • Reverse turn mimetics actually- encompass mimetics of related structures, including gamma turns, beta turns, beta hairpins, and beta bulges.
  • mimetic gamma turns include those represented by the structural formulae:
  • Z H or CH 3
  • Y CH 2 , NH, O, or NCH 3
  • R 1 , R 2 , R 3 and R 4 is H or naturally occurring or synthetic amino acid side chains or analogs thereof.
  • Gamma turn mimetics according to the invention are prepared by directly linking together first and third modular component pieces without the use of a second modular component piece.
  • the synthesis of gamma turn mimetics uses the same synthesis techniques described above for preparing beta turn mimetics including coupling a support- bound first modular component piece to a third modular component piece using silicon mediated acid fluoride coupling.
  • Mimetics of actual beta-turns include those represented by the structural formulae:
  • Y CH 2 , NH, O, or NHCH 3
  • Z H or CH 3
  • R 1 , R 2 , R 3 and R 4 is H or a naturally occurring or synthetic amino acid side chain or an analog thereof.
  • beta bulge mimetics include the following structures:
  • Beta bulge mimetics according to the invention are prepared by linking two second modular component pieces between the first and third modular component pieces.
  • the synthesis of beta bulge mimetics uses the same synthesis techniques described above for preparing beta turn mimetics including coupling the support-bound first modular component piece to the second modular component piece using silicon mediated acid fluoride coupling.
  • X - a linker group selected from the group described previously.
  • the invention provides both reverse turn mimetics having variable sizes and bond angles and variable side chain constituents, and peptides containing such reverse turn mimetics internally or at either end.
  • Such reverse turn mimetics, or peptides containing the same are conformationally restricted, and as such are useful for the design and synthesis of conformationally restricted antigens for making synthetic vaccines or for making antibodies for diagnostic, catalytic or therapeutic purposes.
  • Synthetic nonpeptide molecules can be produced based upon information obtained from nuclear magnetic resonance (NMR) to determine binding interactions and bound-state conformations of these structures that can be inferred from the solution structure.
  • NMR nuclear magnetic resonance
  • this invention provides various methods for screening and evaluating reverse turn mimetics.
  • Reverse turn mimetics are thought to play critical roles in a number of molecular recognition events. Many occasions arise where either a short linear peptide or short peptide fragment of a protein has shown significant biological activity. However, the determination of the bound structure of that peptide at its receptor is a very difficult task. Due to the multiple low energy conformations that linear peptides may adopt, its solution conformation may not accurately reflect its bound conformation. To overcome— this problem a screening method has been developed that uses peptides with conformationally restricted reverse turns mimetics incorporated" therein.
  • 96 octapeptides can be synthesized with various constraints built in.
  • the following reverse turn mimetics represent a portion of the reverse turn compounds that can be synthesized.
  • An alternative method of screening is used where a novel receptor has been cloned or expressed and the endogenous ligand is unknown, and a receptor agonist or antagonist is sought.
  • a method for determining an agonist or antagonist is to generate a large random library of peptides incorporating conformationally constrained reverse turns and to screen this library with the receptor.
  • a number of groups have developed combinatorial library screening approaches, however for purposes of this invention, a modification of the Houghten (R.A. Houghten, et al. , Nature 364:84 (1991)) system is preferred.
  • the first step in the screening method is to synthesize a dipeptide or a random mixture of dipeptides and divide the dipeptide or mixture thereof into, for example, twenty portions, or "tea bags".
  • Each of the 20 is coupled with a different first modular component.
  • the twenty “tea bags” are combined, mixed and then split into 20 tripeptide mixture portions and coupled with 20 different second modular component pieces.
  • the third modular component piece in the first round of screening have no R 2 group in the i+2 position as this is most commonly occupied by Pro or Gly and omitting it simplifies the synthesis.
  • Up to 8,000 different combinatorials attached to the dipeptide or dipeptides have now been produced which are subsequently cyclized to produce reverse turn mimetics of this invention.
  • one, two or more amino acids can be added onto the N-terminus in a random fashion which will provide millions of combinatorials to screen with the known receptor before or after cleavage from the resin.
  • the peptides which bind with the highest affinity can then be sequenced by FAB MS/MS techniques.
  • the lead component can be structurally assayed by various techniques including nuclear magnetic resonance (NMR) .
  • NMR conformational analysis for small peptide and peptide analog systems in solution is straightforward and well known in the art. For example, see Bax, Two-Dimensional Nuclear Magnetic Resonance in Liquids. D. Reidel Publishing Co., Boston, 1982; Wuthrich, NMR of Proteins and Nucleic Acids. Wiley-Interscience, New York, 1986; Ernst et al. , Principles of Nuclear Magnetic Resonance in One and Two Dimensions. Oxford University Press, New York, 1987.
  • NMR nuclear magnetic resonance
  • Identifying the interactions required for binding facilitates preparation of synthetic molecules that are capable of similar X5 binding, and therefore of acting as agonists or antagonists.
  • the identification of a stable bound conformation greatly facilitates the preparation of a synthetic therapeutic agent capable of acting as either an agonist or antagonist for one skilled in the art.
  • the invention provides synthetic therapeutic molecules capable of acting as agonists or antagonists, wherein such molecules are based upon structural features of a conformationally restricted reverse turn mimetic that is capable of binding to the receptor.
  • Particularly likely candidates for the development of such therapeutics include synthetic molecules based upon one or more structural features of a binding conformation of a peptide hormone, lymphokine, growth factor, enzyme inhibitor, or viral binding protein.
  • Example 1 Synthesis of a First Modular Component Piece First modular component pieces were synthesized according to the following schemes.
  • Example 2 Examples 2-5 detail various methods for synthesizing linkers of this invention.
  • First modular component pieces of this invention other than those synthesized in Example 1 can be produced from the linkers of Examples 2-5 by a facile reductive animation reaction, as described by Gribble and Nutaitis, Org. Prep. Proced. Int. 2: 317, (1985), or Sasaki and Coy, Peptides £: 119 (1987).
  • Aldehydes were synthesized from their corresponding carboxylic acids according to the following scheme.
  • Example 5 Preparation of Cis Olefin by Lindlar Reduction of Acetylene Acetylenes prepared according to Example 4 were used in the Lindlar reduction to prepare cis-isomers.
  • Third modular component pieces synthesized according to this example are use to create mimetics having R 2 attached to a carbon atom adjacent to a secondary nitrogen atom.
  • third modular component pieces may be synthesized by the following scheme.
  • D-aspartic acid dimethylester hydrochloride (2.00 g, 10.1 mmol), t- butyldimethylsilyl chloride (1.68 g, 11.1 mmol) and 4- dimethylaminopyridine (62 mg. 0.51 mmol) were dissolved in 50 ml of methylene chloride.
  • triethylamine (3.24 ml, 23.3 mmol) at room temperature slowly and the mixture was allowed to stir overnight at room temperature.
  • the mixture was washed with aqueous ammonium chloride, saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated ia vacuo. The residue was dissolved in 50 ml of ether.
  • a solution of lithium diisopropyl amide (2.5 mmol in 25 ml of THF) was prepared in the usual manner at 0°. After cooling to -78°C, a solution of azetidinone 5. (323 mg, 1 mmol) in 10 ml of THF was added dropwise and allowed to stir for 30 minutes at -78°C. To this was added 400 ml (4 mmol) of butenyl bromide. Stirring was continued for 18 hr. and the reaction allowed to come to room temperature. The reaction mixture was poured into saturated NH*C1 solution and extracted 3 times with 50 ml portions of ether, dried over Na 2 S0_, and the solvent removed in vacuo. The residue was chromatographed on 15 g of silica gel to provide 294 mg, 78% of azetidinone 6.
  • the azetidinone acid (7) produced in Example 9 (238 mg, 0.59 mmol) was dissolved in 30 ml THF and cooled to 0°C. To this solution was added NMM (147 ⁇ l, 2.25 equiv.) and iBuOCOCl (81 ⁇ l,
  • the carboxylic acid potassium salt (h) (38 mg, 0.05 mmol) was dissolved in 400 ⁇ l 1:1 THF:H 2 0. To this was added EDC (11 mg, 1.1 equiv.), HOBT (7.5 mg, 1.1 equiv.) and the protected dipeptide (i) (45 mg, 0.1 mmol) and the reaction was stirred at room temperature for 24 hours. Removal of the volatiles in vacuo and silica gel chromatography (50:1 CH 2 Cl 2 :Me0H) afforded 62% yield of the protected analog.
  • EXAMPLE 13 Assessment of Inhibition of gpl20 binding For measuring binding, fluoresceinated gpl20 was incubated with mimetic K (See Example 12 or Figure 5) or with soluble CD4 at- 22°C in binding buffer (Ca 2+ , Mg 2+ free HBSS, 0.5% BSA, 0.05% sodium azide, pH 7.4). Approximately 300,000 cells (from a 10xl0 7 cell/ml stock) were added to tubes at 4°C in binding buffer, with a final volume of 100 microliters. Samples were incubated at 4°C for 40 min. washed in binding buffer and analyzed in FACS immediately.
  • mimetic K See Example 12 or Figure 5
  • binding buffer Ca 2+ , Mg 2+ free HBSS, 0.5% BSA, 0.05% sodium azide, pH 7.4
  • EXAMPLE 14 Inhibition of Svncvtium Formation Sup Tl cells (see Weiner et al., Pathobiology 4: 1-20 (1991)) were used as target cells for infection. Dilutions (1:2) of soluble CD4, CD4 mimetic, or CD4 peptide were made in 96 well plates in RPMI 1640 media containing 10% fetal calf serum. H9/IIIB infected cells were then plated at a density of approximately 10* cells per well. Sup Tl target cells were then added (5 x 10 5 per well) and syncytium formation was qualitatively and quantitatively determined after a 3 day incubation period.
  • EXAMPLE 15 This example details the liquid phase synthesis of a reverse turn mimetic of this invention. The synthesis is broken down into synthesis steps for easy understanding and the various chemical intermediates are given letter designations. The end product of the synthesis, intermediate product (N') has also been prepared using the solid phase synthesis techniques of this invention. 3*.
  • intermediate compound (B') Twenty-four grams of intermediate compound (B') were dissolved in 80 ml of freshly distilled MeOH to produce a first solution.
  • a second solution was prepared by dissolving 70 mg silver benzoate and 3 ml of methanol and thereafter 500 microliters of Et 3 N was added to the second solution.
  • the second silver benzoate solution was dripped into the first solution and the mixture was stirred for two hours.
  • the volatiles were removed from the mixture under reduced pressure and the residue was dissolved in 400 ml CH 2 C1 2 .
  • the dissolved reactants were washed twice with 100 ml of a hydrochloric acid solution, twice with 100 ml of a saturated NaHC0 3 solution, with 100 ml of water and with 75 ml of saturated NaCl.
  • intermediate product (C) 12.12 grams was dissolved in 40 ml EtOAc under an argon atmosphere. The solution was cooled to 0°C and 17 ml of a cold saturated HCl ⁇ Et0Ac was added to the chilled solution. The mixture was stirred to room temperature. The volatiles were removed under reduced pressure and dried under high vacuum at approximately 40°C for three hours resulting in intermediate product (D*) a tan crystalline solid.
  • the solution was diluted to 700 ml with Et 2 0 and washed twice with 150 ml of water and the combined aqueous layers were extracted with 300 ml of Et 2 0. The combined organic layers were washed with saturated NaCl and then concentrated down to 20 ml. 200 ml of a 30/70 mixture of ethyl acetate ⁇ hexane was added to the 20 ml of concentrated solution and the mixture was filtered through a silica gel pad and the pad was washed with 100 ml of the 30/70 solution. The volatiles were removed to yield intermediate (E*).
  • Intermediate product (H') was dissolved in 50 ml of methanol and 30 mg of 5% Pd ⁇ C was added to the solution. The solution was shaken for 12 hours under a 50 psi hydrogen atmosphere. The solution was then filtered through celite, concentrated, and dried at high vacuum overnight to yield intermediate product (I') , a clear oil consisting of a second and third modular component piece of this invention.
  • intermediate product (M' ) 60 mg was mixed with 95 mg (192 micromoles, 1.3eq.) FMOC-Tyr acid fluoride, 103 mg (768 micromoles, 4eq of AgCN in a 10 ml. rb with a reflux condenser under an argon atmosphere. The mixture was dried under high vacuum at 40°C for 6 hours. 4.5 ml of freshly distilled benzene was added to the mixture under an argon atmosphere and the mixture was heated at gentle S
  • the silicon mediated acid fluoride coupling step of the solid phase synthesis method of this invention is performed as follows:
  • the resin After coupling the first modular component piece, the resin is reacted with 5eq of bis-trimethylsilyl acetamide as a solution in THF for 15 minutes. The resulting resin is washed with THF. A solution of acid fluoride in THF was then prepared according to the method of Carpino and Han, JACS 1990, (9651-52) and is added to the resin solution and the resulting reaction is allowed to proceed until it is complete as judged by the Kaiser ninhydrin assay.
  • This solid phase acid fluoride coupling procedure provides nearly quantitative acylation of the hydrazine nitrogen whereas all other coupling procedures attempted provide, at best, less than 20% acylation after exhaustive coupling.
  • the resin is attached to the X 1 component of a first modular component.
  • X 1 may be selected from the group NH and 0. Additionally, the selection of protective group, e.g., FMOC of BOC is not critical to the synthesis method.
  • HIV gpl20 V3 loop which comprises the PND (principal neutralizing determinant) can exist in one of the following two reverse turn conformations.
  • R' is or

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Abstract

L'invention concerne des bactériaux et des procédés permettant d'effectuer la synthèse de nouveaux agents mimétiques de girations inverses, ainsi que des peptides les contenant. L'invention décrit également de nouvelles molécules thérapeutiques synthétiques non peptides conçues sur la base d'interactions entre les agents mimétiques de girations inverses ou des peptides les contenant, et des récepteurs, anticorps ou enzymes.
PCT/US1993/007447 1992-08-06 1993-08-06 Agents mimetiques restreints dans leur conformation de girations inverses, et peptides les contenant WO1994003494A1 (fr)

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AU50006/93A AU679460B2 (en) 1992-08-06 1993-08-06 Conformationally restricted mimetics of reverse turns and peptides containing the same
EP93919936A EP0656907A1 (fr) 1992-08-06 1993-08-06 Agents mimetiques restreints dans leur conformation de girations inverses, et peptides les contenant
JP6505602A JPH07509723A (ja) 1992-08-06 1993-08-06 反転型ターンの立体配座的に拘束されたミメティックスと前者を含有するペプチド
KR1019950700471A KR950703000A (ko) 1992-08-06 1995-02-06 구조적으로 제한된 역회전 모사체 및 이를 함유하는 펩타이드(conformationally restricted mimetics of reverse turns and peptides containing the same)

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WO1995025120A1 (fr) * 1994-03-15 1995-09-21 Molecumetics, Ltd. Vaccins peptidiques et methodes associees
WO1996022304A1 (fr) * 1995-01-20 1996-07-25 Molecumetics, Ltd. Bibliotheque de substances mimetiques de retournement astreintes a une conformation et procedes associes
WO1997015577A1 (fr) * 1995-10-27 1997-05-01 Molecumetics Ltd. Agents mimetiques a rotation inverse et procedes correspondants
WO1998049168A1 (fr) * 1997-04-30 1998-11-05 Molecumetics Ltd. Mimetiques a rotation inverse et procedes associes
WO2001000210A1 (fr) * 1999-06-25 2001-01-04 Molecumetics Ltd. Mimetiques de coudes inverses et methodes associees
US6271198B1 (en) 1996-11-06 2001-08-07 Genentech, Inc. Constrained helical peptides and methods of making same
US6294525B1 (en) 1999-09-01 2001-09-25 Molecumetics Ltd. Reverse-turn mimetics and methods relating thereto
US6762185B1 (en) 2002-03-01 2004-07-13 Choongwae Pharma Corporation Compounds useful for treatment of cancer, compositions containing the same, and methods of their use
US6914123B2 (en) 2001-04-17 2005-07-05 Genentech, Inc. Hairpin peptides with a novel structural motif and methods relating thereto
US6943157B2 (en) 2001-10-09 2005-09-13 Myriad Genetics, Inc. Reverse-turn mimetics and composition and methods relating thereto
US7008941B2 (en) 2001-05-16 2006-03-07 Myriad Genetics, Inc. Reverse-turn mimetics and methods relating thereto
US7232822B2 (en) 2001-10-12 2007-06-19 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
US7235626B1 (en) 1999-06-14 2007-06-26 Genentech, Inc. Structured peptide scaffold for displaying turn libraries on phage
US7345040B2 (en) 2002-10-17 2008-03-18 Myriad Genetics, Inc. Reverse-turn mimetics and compositions and methods relating thereto
WO2009051397A2 (fr) 2007-10-15 2009-04-23 Choongwae Pharma Corporation Nouveaux composés de structures mimétiques de coude inverse et leur utilisation (3)
US7531320B2 (en) 2003-08-28 2009-05-12 Choongwae Pharma Corporation Modulation of β-catenin/TCF-activated transcription
EP2060580A1 (fr) * 2007-11-19 2009-05-20 SOLVAY (Société Anonyme) Procédé de préparation de peptides persilylés
US7566711B2 (en) 2001-10-12 2009-07-28 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
US7576084B2 (en) 2001-10-12 2009-08-18 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
WO2009148192A1 (fr) 2008-06-06 2009-12-10 Prism Biolab Corporation Structures mimétique d’hélice alpha et procédés associés
US7662960B2 (en) 2001-04-26 2010-02-16 Choongwae Pharma Corporation Beta-strand mimetics and method relating thereto
WO2010044485A1 (fr) 2008-10-14 2010-04-22 Prism Biolab Corporation Mimétiques d'hélice alpha dans le traitement du cancer
WO2011096440A1 (fr) 2010-02-03 2011-08-11 ＰＲＩＳＭ ＢｉｏＬａｂ株式会社 Composé capable de se lier à une protéine dénaturée d'origine naturelle, et procédé de criblage du composé
US8080657B2 (en) 2001-10-12 2011-12-20 Choongwae Pharma Corporation Compounds of reverse turn mimetics and the use thereof
KR20120028877A (ko) 2009-04-15 2012-03-23 제이더블유중외제약 주식회사 리버스턴 유사체의 신규한 화합물 및 그 제조방법과 용도
WO2012050393A2 (fr) 2010-10-14 2012-04-19 제이더블유중외제약 주식회사 Nouveau composé à mimétique inverse, procédé de production, et utilisation de ce composé
WO2012115286A1 (fr) 2011-02-25 2012-08-30 Prism Biolab Corporation Mimétiques d'hélice alpha et procédés s'y rapportant
WO2015056104A2 (fr) 2013-10-18 2015-04-23 Hiroyuki Kouji Traitement de la fibrose hépatique à l'aide d'un inhibiteur de la cbp/caténine
US9040531B2 (en) 2009-05-07 2015-05-26 Prism BioLab Co., Ltd. Alpha helix mimetics and methods relating thereto

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US7235626B1 (en) 1999-06-14 2007-06-26 Genentech, Inc. Structured peptide scaffold for displaying turn libraries on phage
WO2001000210A1 (fr) * 1999-06-25 2001-01-04 Molecumetics Ltd. Mimetiques de coudes inverses et methodes associees
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JPH07509723A (ja) 1995-10-26
AU679460B2 (en) 1997-07-03

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