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USRE40987E1 - Cyclosporin with improved activity profile - Google Patents

Cyclosporin with improved activity profile Download PDF

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Publication number
USRE40987E1
USRE40987E1 US12/123,601 US12360199A USRE40987E US RE40987 E1 USRE40987 E1 US RE40987E1 US 12360199 A US12360199 A US 12360199A US RE40987 E USRE40987 E US RE40987E
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Prior art keywords
cyclosporin
thr
val
solution
coome
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Roland M. Wenger
Manfred Mutter
Thomas Rückle
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Debiopharm SA
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Debiopharm SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel cyclosporin (Cs), the pharmaceutical use thereof and to a pharmaceutical composition containing it.
  • Cyclosporins are a class of cyclic poly-N-methylated undecapeptides having several pharmacological activities; in particular, they are immunosuppressants, anti-inflammatories, anti-parasitic agents, drug resistance suppressors (anti-MDR) and anti-viral agents.
  • the first cyclosporin isolated from a fungal culture is cyclosporin A which is found in the natural state and which is represented by the following formula:
  • Cyclosporin A isolated 20 years ago from Tolypocladium inflatum has considerable immunosuppressive activity. It has revolutionised organ transplantation and is commonly used in the treatment of autoimmune diseases.
  • CsA Cyclosporin A
  • CsA results mainly in the selective suppression of the activation of T lymphocytes.
  • This immunosuppressive activity is explained by the fact that CsA binds to an intracellular proteic receptor cyclophilin A (CyP), forming a CyP-CsA complex which interacts with calcineurin (CaN) and thus inhibits its phosphatase activity.
  • CyP proteic receptor cyclophilin A
  • CaN calcineurin
  • the transcription of families of genes exhibiting precocious activation will be blocked (cf. O'Keefe, S. J; Tamura, J; Nature 1992, 357, 692-694).
  • the present invention provides the production of a novel cyclosporin with considerable HIV-1 (human immunodeficiency virus) inhibitory activity and not having the immunosuppressive activity of CsA.
  • the mode of infection of HIV type 1 is unique amongst the retroviruses because it requires the specific incorporation into its virion of the cellular protein CyP which interacts with the polyprotein Gag (cf. Eltaly Kara Franke, Bi-Xing Chem. Journal of Virology, September 1995, vol. 69 no. 9). It is well known that CyP binds to CsA and CaN in a ternary complex. However, the native function of CyP is to catalyse the isomerisation of peptidyl-prolyl bonds, a limiting and important step in the process allowing proteins to acquire a definitive three-dimensional structure. CyP also protects cells from thermal shocks or acts as a chaperone protein.
  • the product of the Gag gene of HIV-1 prohibits the formation of a ternary complex with CyP and CaN.
  • the HIV virus needs CyP in order to bind to the product of the Gag gene so as to form its own virions (cf. Franke, E. K; 1994 Nature 372, 359-362).
  • CsA there is direct competition with the polyprotein derived from the Gag gene of HIV-1 to bind the CyP. This CsA acts at two levels on the replication of the viral cycle. Firstly, at the level of translocation towards the core of the pre-integrated complex, then in the production of infectious viral particles.
  • Another patent WO 97/04005 uses the method of preparation of the patent EP 484 281 and the method developed by Seebach EP 194972 in order to produce derivatives in position 3 such as, for example, (D)-MeSer 3 -(4-OH)MeLeu 4 cyclosporin.
  • This substance has a better affinity for CyP but only has limited anti-HIV activity compared with the reference derivative MeIle 4 -Cs (NIM 811). The more hydrophilic nature of this substance prevents it penetrating the cells and the organism. This is reflected directly in the reduced anti-HIV activity of this substance (cf. Cristos Papageorgiou, J. J. Sanglier and RenéTraber—Bioorganic & Medicinal Chemistry Letters, Vol. 6, No. 1, pp. 23-26, 1996).
  • FIG. 1 shows the general structure of the novel cyclosporin according to the invention
  • FIGS. 2 and 3 show analysis spectra for NEtIle4-Cs
  • Table I shows affinity results of Cs derivatives for cyclophilin A in a competitive ELISA test
  • Table II shows the percentage protection during HIV infection of a CEM-SS cell line
  • TABLE III shows examples of cyclosporins with different groups R1, R2, R3 and R4.
  • the substances described in this invention have the dual advantage of retaining the same affinity for CyP as that observed with [(4-OH)MeLeu 4 ]-Cs or cyclosporin A whilst having anti-HIV activity which is identical to or greater than that of the reference derivatives (MeVal 4 -Cs or MeIle 4 -Cs) and appreciably greater than the anti-HIV activity of cyclosporin A or of (4-OH)MeLeu 4 -Cs.
  • the object of the invention is to provide a novel cyclosporin which does not have the immunosuppressive activity of CsA and has an improved profile of activity.
  • This new family of Cs is characterised by the formula (I): wherein:
  • the new cyclosporin molecule thus obtained offers the unexpected and surprising advantage of having much better stability towards metabolisation than all the other cyclosporins known hitherto.
  • This new molecule is much more resistant to the phenomena of oxidation and degradation which take place in the cell. Consequently, the “in vivo” life of this new N-alkyl as Cs is particularly prolonged.
  • this new N-alkyl aa 4 cyclosporin has high affinity for CyP and has anti-HIV activity which is equal to or greater than the best existing cyclosporins.
  • FIG. 1 represents the general structure of this novel cyclosporin.
  • the groups R1, R2, R3 and R4 will be largely described in Table III.
  • Table III Thus, by transforming these 4 key positions, it was possible to retain a very good affinity for cyclophilin and to prevent the formation of a ternary complex with CaN and, above all, to increase, in a particularly advantageous manner, its stability towards enzymatic oxidation and consequently its anti-HIV activity.
  • This novel cyclosporin is thus characterised principally by the presence, in position 4, of a residue with R>CH 3 and R ⁇ C 10 H 21 .
  • the substituent of nitrogen used will be, for example, ethyl, propyl, butyl or pentyl, but these examples are not limiting.
  • This novel cyclosporin is particularly active if the residue in position 4 is an N-ethylated amino acid (see drawings 2 and 3).
  • the invention also claims the pharmaceutical composition of the substance as described by formula (I). This may be combined with a pharmaceutically acceptable solution.
  • the pharmaceutical formulation thus produced makes it possible to increase the solubility in water or to keep the composition in the form of microemulsions in suspension in water.
  • the object of the present invention is also to provide a new medicinal product which may be used, for example, in the treatment and prevention of AIDS (acquired immunodeficiency syndrome).
  • AIDS immunodeficiency syndrome
  • the cyclosporin modified in position 4 by a residue Z, namely N-ethyl-valine will be used in particular for the production of a medicinal product intended for the treatment and prevention of AIDS.
  • the application for the prevention of AIDS is not limiting.
  • This substance may also be used, for example, for its anti-inflammatory properties.
  • CsA The process for the synthesis of CsA is described in: R. Wenger (Helv. Chim. Acta Vol. 67, p. 502-525 (1984)).
  • the process for opening protected cyclosporin A (OAc) is described in Peptides 1996.
  • the CsA molecule is treated with Meerwein's reagent (CH 3 ) 3 OBF 4 then cleaved by treatment with acid in methanol or hydrolysed by water in order to convert it to a linear peptide of 11 amino acid residues: H-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-MeBmt(OAc)-Abu-Sar-OCH3.
  • the product is then used for the following synthesis routes without an additional purification step.
  • This substance is hydrolysed then activated and condensed with 1 corresponding amino acid in order to produce a new peptide with 11 residues, the starting product for the cyclisation and production of a novel cyclosporin with the desired properties.
  • the crude product (900 mg) is purified by chromatography [150 g of silica gel (0.4-0.63)], use of dichloromethane/methanol/triethylamine (17:3:0.05) as eluants) to eluate 700 mg (95%) of pure, deprotected undecapeptide (4).
  • the trimethyloxoformate is evaporated under vacuum and the remainder of the aqueous solution is diluted in 300 ml of water. This solution is then extracted 2 ⁇ with 100 ml of diethylether. The organic phase is then re-extracted 3 ⁇ with a 0.1 N aqueous solution of HCl. The combined aqueous phases are cooled to 0° C. then the pH is adjusted to 9 using (2N)NaOH. The solution then becomes cloudy. The aqueous suspension is extracted 4 ⁇ with 100 ml of diethylether. The combined organic phases are then dried with Na 2 SO 4 , filtered and the solvent is finally evaporated.
  • the results of Table 1 show the affinity of the derivatives of Cs for cyclophilin A in a competitive ELISA test described by Quesniaux in Eur. J. Immunology 1987, 17, 1359-1365.
  • Cs bound to BSA serum albumin
  • the concentration required to obtain 50% inhibition (IC 50 ) of the reference reaction in the absence of competitor is then calculated.
  • the results are expressed by the binding index BI which is the ratio of the IC 50 of the derivative and the IC 50 of CsA.
  • a binding index (BI) of 1.0 indicates that the compound tested binds as well as CsA.
  • a value lower than 1.0 indicates that the derivative binds better than CsA, and a value greater than 1.0 means that the derivative binds less well to CyP than CsA.
  • Cs is regarded as being immunosuppressive if its activity in the mixed lymphocyte reaction (MLR) is greater than 5%.
  • MLR mixed lymphocyte reaction
  • the reaction (MLR) is described by T. Meo in “Immunological Methods”, L. Lefkovits and B. Devis, Eds, Académie Prev. N.Y. pp: 227-239 (1979).
  • Spleen cells (0.5.10 6 ) originating from Balb/c mice (female, 8 to 10 weeks) are co-incubated for 5 days in the presence of treated spleen cells originating from CBA mice (females, 8 to 10 weeks). These cells were treated with mitomycin C or were irradiated at 2000 rads. The non-irradiated allogenic spleen cells exhibit a proliferative response in Balb/c cells which can be measured by incorporating a labelled precursor in the DNA. If the stimulator cells are irradiated (or treated with mitomycin C), the Balb/c cells no longer exhibit a proliferative response but retain their antigenicity.
  • the IC 50 calculated in the MLR test is compared with the IC 50 corresponding to CsA in a parallel experiment.
  • the IR index is thus found, this being the ratio of the IC 50 of the MLR test of the derivatives over the IC 50 of cyclosporin A.
  • a value of 1.0 for the IR means an activity similar to CsA.
  • a lower value means better activity and a value greater than 1.0 shows that the activity of the compound is lower than that of CsA.
  • Table II describes the percentage protection during infection with HIV of a CEM-SS cell line.
  • the protection of this line in the presence of a Cs derivative is compared with the infection of a line cultivated in the absence of Cs (reference control).
  • a mean value is established at a concentration of the derivative of 2 ⁇ 10 ⁇ 6 molar. This anti-HIV activity was measured by the NCI (National Cancer Institute) in Washington in the USA.

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US12/123,601 1998-07-01 1999-06-30 Cyclosporin with improved activity profile Expired - Lifetime USRE40987E1 (en)

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CH140598 1998-07-01
US09/720,923 US6927208B1 (en) 1998-07-01 1999-06-30 Cyclosporin with improved activity profile
PCT/IB1999/001232 WO2000001715A1 (fr) 1998-07-01 1999-06-30 Nouvelle cyclosporine ayant un profil d'activite ameliore

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US (2) USRE40987E1 (fr)
EP (1) EP1091975B1 (fr)
JP (1) JP4350898B2 (fr)
CN (1) CN1218958C (fr)
AT (1) ATE312843T1 (fr)
AU (1) AU759480B2 (fr)
BR (1) BR9911724A (fr)
CA (1) CA2335903C (fr)
DE (1) DE69928938T2 (fr)
DK (1) DK1091975T3 (fr)
ES (1) ES2255275T3 (fr)
MX (1) MXPA00013019A (fr)
PT (1) PT1091975E (fr)
WO (1) WO2000001715A1 (fr)

Cited By (2)

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US20130267460A1 (en) * 2010-09-16 2013-10-10 The Johns Hopkins University Methods of Inhibiting Alphavirus Replication and Treating Alphavirus Infection
US20160051625A1 (en) * 2009-01-30 2016-02-25 Enanta Pharmaceuticals, Inc. Cyclosporin analogues for preventing or treating hepatitis c infection

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