WO2009083929A1 - Inhibiteurs de caspase-1 et utilisations de ceux-ci - Google Patents

Inhibiteurs de caspase-1 et utilisations de ceux-ci Download PDF

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Publication number
WO2009083929A1
WO2009083929A1 PCT/IB2008/055561 IB2008055561W WO2009083929A1 WO 2009083929 A1 WO2009083929 A1 WO 2009083929A1 IB 2008055561 W IB2008055561 W IB 2008055561W WO 2009083929 A1 WO2009083929 A1 WO 2009083929A1
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WO
WIPO (PCT)
Prior art keywords
treat
prevent
caspase
disease
activity
Prior art date
Application number
PCT/IB2008/055561
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English (en)
Inventor
David Chauvier
Etienne Jacotot
Original Assignee
Theraptosis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Theraptosis filed Critical Theraptosis
Publication of WO2009083929A1 publication Critical patent/WO2009083929A1/fr

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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
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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 invention is in the field of medicinal biology and chemistry and relates to novel derivatives having inhibitory properties with respect to caspase-1 and their biological applications particularly to treat diseases and injuries where caspase-1 activity is implicated.
  • the invention thus relates to new caspase-1 inhibitors.
  • the derivatives of the invention have both peptide and organic entities, wherein the peptide entity is a tetrapeptide YVAD of sequence SEQ ID N° 1 ((S)- ⁇ yr-(S)-Val-(S)-Aia.-(R,S)-Asp), the Asp residue being optionally substituted by O-methyl group (OMe) and has terminal organic end units respectively substituted by quinolinylcarbonyl and 2,6-difluorophenyl ester backbones.
  • the peptide entity is a tetrapeptide YVAD of sequence SEQ ID N° 1 ((S)- ⁇ yr-(S)-Val-(S)-Aia.-(R,S)-Asp)
  • Asp residue being optionally substituted by O-methyl group (OMe) and has terminal organic end units respectively substituted by quinolinylcarbonyl and 2,6-difluorophenyl ester backbones.
  • the invention relates to a derivative of formula (I) 5-(2,6-Difluoro-phenoxy)-3(R,S)-[2(S)-(2(S)- ⁇ 3-(4-hydroxy-phenyl)-2(S)-[(quinoline-2- carbonyl)-amino] -propionylamino ⁇ -3 -methyl-butyrylamino)-propionylamino] -4-oxo- pentanoic acid methyl ester, or Quinoline-2-carbonyl-fS>Tyr-fS>Val-fS>Ala- ⁇ -Asp(OMe)-CH2OC6H3(2,6-F 2 ).
  • the above derivatives are under salt form such as chlorhydrate.
  • the invention also relates to derivatives of formula (II) derived from those of formula (I),
  • R 2 , R 3 ,R 4 and R 5 are natural or non natural amino acid side chains;
  • P4, P3, P2 and Pl are preferentially and respectively, Tyrosine, Valine, Alanine and Aspartate;the aspartate moiety being optionally methylated;
  • R 1 and R 2 are a hydrogen atom, deuterium atom, Ci_2o aliphatic, substituted or unsubstituted aryl, cycloalkyl, naphthyl, substituted naphthyl, 2-benzoxazolyl, substituted 2-oxazolyl, (CH 2 ) n cycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n substituted phenyl,
  • R 3 , R 4 , R 5 , R 6 and R 7 are Ci_ 2 o aliphatic, cycloalkyl, naphthyl, substituted naphthyl,
  • 2-benzoxazolyl substituted 2-oxazolyl, (CH 2 ) n cycloalkyl, (CH 2 ) n phenyl,
  • R 6 and R 7 are malonyl, methylmalonyl, 2-quinolinylcarbonyl, succinyl, methylsuccinyl, acetyl, 2-quinolinylmalonyl group;
  • R 6 is a hydrogen atom and R 7 is R, U, C0(CH 2 ) n NH(U), CO(CH 2 ) n S(U);
  • U is unsubstituted or substituted (2-, 3-, 4-, 5-, 6-, 7- or 8-) quinolinyl, Ci_ 2 o straight chain or branched alkyl, (CH 2 ) n cycloalkyl, (CH 2 ) n phenyl, (CH2) n substituted phenyl, (CH 2 )I 1 (I- or 2- naphthyl), (CH2) n heteroaryl, biotin, dinitrophenyl (DNP), iodoacetamides, DTNB, COR (ex.
  • Alexa Fluor 488 Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 555, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700, Alexa Fluor 750....
  • Q-DOTs TM derivatives (655,605, 585,525,...)
  • SNARF ZenonTM derivatives (ZenonTM Alexa Fluor® 350, ZenonTM Alexa Fluor® 488, ZenonTM Alexa Fluor® 555, ZenonTM Alexa
  • Biotin-XX ZenonTM R-Phycoerythrin, ); NBD, Texas Red ®, QS Y® dyes
  • EBFP GFP wild type, QFP mutants H9/P4/P9/P11/W, GFPuv, ECFP, Y66W, S65A, S65C, S65L, S65T, EGFP, EYFP, ECFP, DsRedl, DsRed2, NANOGOLD ® particules, streptavidin-Nanogold ® , Monomaleido Nanogold®, Mono-Sulfo-NHS- Nanogold®, Monoamino Nanogold®, positively/negatively charged Nanogold® (NN, NHSN, NHSNA, NHSNS), Non-Functionalized Nanogold®, Monomaleido
  • Nanogold® Mono-Sulfo-NHS-Nanogold®, Monoamino Nanogold®, Nonfunctional Nanogold®, Nanogold®-conjugates, Nanogold®-streptavidin, lipide- Nanogold (Palmitoyl Nanogold®, DPPE Nanogold®, Palmitoyl Undecagold, DPPE Undecagold), Ni-NTA-Nanogold®, Alexa Fluor® 488 FluoroNanogold, Alexa Fluor® 594 FluoroNanogold, Fluorescein FluoroNanogold, HRP substrate-
  • R 7 and R 6 are also taken together with the intervening nitrogen to form a heterocyclic ring such as substituted or unsubstituted tetrahydroquinoline, tetrahydroisoquinoline, dihydroacridine, benzazepine, pyrrolidine, morpholine, thiomorpholine, piperazine, piperidine, dihydropyridine, benzimidazole, imidazole, imidazoline, pyrrole, pyrrolidine, pyrroline, pyrazole, pyrazoline, pyrazolidine, triazole, piperidine, morpholine, thiomorpholine, piperazine, carbazole, phenothiazine, phenoxazine, dihydrophenazine, dihydrocinnoline, dihydroquinoxaline, dihydronaphthyridine, tetrahydronaphthyridine, dihydroacridine, ind
  • R is a hydrogen atom, Ci_2o aliphatic group, aryl, substituted aryl (ex: A- nitrophenyl or coumarine derivatives), hetetoaryl (ex. 2-pyridine), substituted heteroaryl, cycloalkyl, naphthyl, substituted naphthyl, (CH 2 ) n cycloalkyl, (CH2) n phenyl, (CH2) n substituted phenyl (ex: 2,6-dihalophenyl), (CH 2 )I 1 (I- or 2- naphthyl), (CH 2 ) n heteroaryl or (un)substituted (2-, 3-, A-, 5-, 6-, 7- or 8-) quinolinyl, fluorenmethyl ; (xi) Y is an electronegative leaving group including halogens such as F, Cl, Br or I, aryl or alkylsulfonyloxy groups, trifluoromethanes, tri
  • R 1 , R 2 , R 3 ,R 4 ,R 5 ,R 6 and R 7 may include in their structure radio labelling isotopes including (but not restrictively) Chlorine-36, Carbon-14, Tritium , Americium- 241, Caesium-137, Silver-l lOm, Cobalt-60, Lanthanum- 140, Scandium-46, GoId- 198, Cobalt-60, Gold-198, Technetium-99m, Strontium-90, Krypton-85, Thallium-
  • radio labelling isotopes including (but not restrictively) Chlorine-36, Carbon-14, Tritium , Americium- 241, Caesium-137, Silver-l lOm, Cobalt-60, Lanthanum- 140, Scandium-46, GoId- 198, Cobalt-60, Gold-198, Technetium-99m, Strontium-90, Krypton-85, Thallium-
  • R 1 , R 2 , R 3 ,R 4 ,R 5 ,R 6 and R 7 may include (but not restrictively) "cold labeling" in their structure including 13 C, 2 H, 15 N, 19 F, 31 P, 23 Na or 31 K ; (xv) (x) n is 0 to 20.
  • aliphatic herein means straight chained or branched Ci_ 2 o hydrocarbons which are completely saturated or which contain one or more units of unsaturation.
  • alkyl used alone or as part of a larger moiety refers to both straight or branched chains containing one to twenty carbon atoms.
  • aryl refers to mono cyclic or polycyclic aromatic ring groups having five to fourteen atoms, such as phenyl, naphthyl or anthryl.
  • heterocyclic group refers to saturated or unsaturated polycyclic or monocyclic ring systems containing one or more heteroatoms and a ring size of three to nine such as furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxalolyl, isothiazolyl, oxadiazolyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, trithianyl, indolizinyl, indolyl, isoindolyl, ind
  • Heteroaryl refers to a heterocyclic ring that is aromatic.
  • the term “carbocyclic group” refers to unsaturated monocyclic or polycyclic carbon ring systems of three to fourteen carbons which may be fused to aryl or heterocyclic groups.
  • substituents can be halogen (F, Cl, Br, I), OH, U, CO(CH 2 ) n NH(U), CO(CH 2 ) n S(U), OR, SR, NH 2 , NHR, NR 2 , OCOR, OP(O)R 2 wherein R is an aliphatic group, an aryl or substituted group, an aralkyl group, a carbocyclic group, an alkyl carbocyclic group, a heterocyclic group or a radio-isotope (ex: I 125 , H 3 , S 35 , C 14 , P 33 , P 32 , Cr 51 , Ca 45 , Fe 59 , Ni 63 , Ba 133 , Cs 137 , Eu 152 , Ra 226 , Xe 133 , technetium 99, thallium 201).
  • FITC stands for fluorescein isothiocyanate.
  • the invention thus relates to the use of said derivatives as inhibitors for preventing or blocking caspase-1 activity in in vitro or in vivo cell death.
  • said derivatives are used for In vivo inhibition of caspase-1 activity to provide cytoprotective effect.
  • they are used for //? vitro inhibition of caspase-1 activity.
  • the invention also relates to the use of said derivatives as drugs.
  • compositions comprising an effective amount of at least one derivative such as above defined in association with a pharmaceutically acceptable carrier.
  • Said pharmaceutical compositions are useful for administration by oral, nasal, local (intracerebroventricular, intrahippocampal, other intracerebral delivery, intracerebral implantation of instrumentation for mechanical delivery) or systemic (for example: intraperitoneal, intravenous....) administration or intradermic delivery, intrathecal delivery or as aerosol to reduce in vivo liver cell death, but not restricted to these delivery systems. They are administered in amounts adapted to the patient and the disease to be prevented or treated.
  • compositions of the invention are useful to prevent and/or treat oxygen-induced organ damages linked to anoxia, hypoxia or hyperoxia to prevent and/or treat inflammation or inflammatory diseases, inflammatory bowel disease, sepsis and septic shock, or - to prevent and/or treat apoptosis during degenerative diseases including Alzheimer's disease, Huntingtons' disease, Parkinsons' disease, Multiple sclerosis, amyotrophic lateral sclerosis, spinobulbar atrophy, prion disease, dementia; brain hypoxia, anoxia, hyperoxia; ischemic multifocal lesions involving the cortical or lenticulo striate branches of the MCA, ischemic lesions in the territory of the middle cerebral artery (MCA) or left cerebral hemisphere, caused by haemodynamic differences from a patent ductus arteriosus, or a more direct route involving the left common carotid; focal arterial infarction, or to prevent and/or treat retinal pericyte apoptosis
  • treatment or treat means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Figures 1 and 2 representing the caspase-1 activity (%) as a function of inhibitor concentration ( ⁇ M).
  • caspase activity assays were performed as described hereinafter to determine the inhibitory profile of the above derivative of the invention. 25U of human (caspase-1 to -10 and -14; Bio mo 1, Plymouth, Pennsylvania, USA) or rodent (mouse caspase-1, Biovision, Mountain View, USA).
  • An IC50 value corresponding to the concentration that could inhibit 50% of caspase activity was determined from the dose-response sigmoid curve.
  • Specific activity of each caspase was internally controlled with the corresponding specific inhibitors (1-2 ⁇ M, Biomol and MPQBiogene (Illkirsh, France). Calpain inhibitor (E64d, 1 ⁇ M; Sigma) was used as negative control for caspase inhibition.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux inhibiteurs de caspase-1 sélectifs qui reconnaissent la caspase-1 et bloquent son activité fondée sur la SEQ1.
PCT/IB2008/055561 2007-12-27 2008-12-29 Inhibiteurs de caspase-1 et utilisations de ceux-ci WO2009083929A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US914307P 2007-12-27 2007-12-27
US61/009,143 2007-12-27

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WO2009083929A1 true WO2009083929A1 (fr) 2009-07-09

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040209813A1 (en) * 1999-04-06 2004-10-21 Budd Ralph C Caspase inhibitors for inhibiting blood cell proliferation and for treating autoimmune diseases
US20070184021A1 (en) * 2002-10-01 2007-08-09 Daohong Zhou Use of caspase inhibitors as a therapeutic agent against radiation-induced injury

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040209813A1 (en) * 1999-04-06 2004-10-21 Budd Ralph C Caspase inhibitors for inhibiting blood cell proliferation and for treating autoimmune diseases
US20070184021A1 (en) * 2002-10-01 2007-08-09 Daohong Zhou Use of caspase inhibitors as a therapeutic agent against radiation-induced injury

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CORASANITI M T ET AL: "Neuroprotection by the caspase-1 inhibitor Ac-YVAD-(acyloxy)mk in experimental neuroAIDS is independent from IL-1beta generation.", CELL DEATH AND DIFFERENTIATION AUG 2005, vol. 12 Suppl 1, August 2005 (2005-08-01), pages 999 - 1001, XP002526360, ISSN: 1350-9047 *
RABUFFETTI M ET AL: "Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chlorome thyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines.", THE JOURNAL OF NEUROSCIENCE : THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE 15 JUN 2000, vol. 20, no. 12, 15 June 2000 (2000-06-15), pages 4398 - 4404, XP002526361, ISSN: 0270-6474 *

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