WO2009083930A1 - Inhibiteurs de caspase-8 et utilisations de ceux-ci - Google Patents

Inhibiteurs de caspase-8 et utilisations de ceux-ci Download PDF

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Publication number
WO2009083930A1
WO2009083930A1 PCT/IB2008/055564 IB2008055564W WO2009083930A1 WO 2009083930 A1 WO2009083930 A1 WO 2009083930A1 IB 2008055564 W IB2008055564 W IB 2008055564W WO 2009083930 A1 WO2009083930 A1 WO 2009083930A1
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WIPO (PCT)
Prior art keywords
treat
caspase
prevent
disease
inhibitors
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PCT/IB2008/055564
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English (en)
Inventor
David Chauvier
Etienne Jacotot
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Theraptosis
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Publication of WO2009083930A1 publication Critical patent/WO2009083930A1/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
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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 capable of inhibiting in vivo caspase-8. It also relates to their biological applications particularly to treat diseases and injuries where caspase-8 activity is implicated. Researches of the inventors have lead them to develop new derivatives having caspase-8 inhitory properties of great interest.
  • the invention thus relates to new caspase-8 inhibitors.
  • the inventors have shown that new selective caspase-8 inhibitors are capable of preventing or decreasing cell death in in vivo pathological situations including liver hepatitis.
  • the invention relates to new applications for new caspase-8 inhibitors including local delivery or systemic (intraperitoneal, intravenous.%) administration to reduce liver cell death during pathological situations in which liver cells are dying.
  • the invention relates to new applications for new caspase-8 inhibitors including in the field of acute or chronic to reduce liver cell death during pathological situations in which liver cells are dying.
  • the derivatives of the invention have both peptide and organic entities wherein the peptide entity is a tetrapeptide IETD of SEQ ID N°l ⁇ (S) - ⁇ ,QU- (S) -GIu- (2 S, 3 S) - ⁇ hv- (R, S) -As ⁇ ) substituted on aspartate residue by O-methyl group (OMe), and having extremities substituted by quinolinylcarbonyl and 2,6-difluorophenyl ester backbones.
  • IETD tetrapeptide IETD of SEQ ID N°l ⁇ (S) - ⁇ ,QU- (S) -GIu- (2 S, 3 S) - ⁇ hv- (R, S) -As ⁇ ) substituted on aspartate residue by O-methyl group (OMe), and having extremities substituted by quinolinylcarbonyl and 2,6-difluorophenyl ester backbones.
  • a preferred derivative corresponds to 3(R,S)-[2(S)-(4-Carboxy-2(S)- ⁇ 4-methyl-2(S)- [(quinoline-2-carbonyl)-amino]-pentanoylamino ⁇ -butyrylamino)-3(S)-hydroxy- butyrylamino]-5-(2,6-difluoro-phenoxy)-4-oxo-pentanoic acid methyl ester or Quinoline-2- carbonyl-fS>Leu-fS>Glu-f2 ⁇ >Thr- ⁇ 5>Asp(OMe)-CH 2 OC6H3(2,6-F2), and has formula (I):
  • the above derivatives are under a salt form such as chlorydrate.
  • 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 ;
  • P1,P2, P3 and P4 are preferentially and respectively aspartate, threonine, serine and isoleucine; aspartate may be or not methylated ;
  • R 1 and R 2 are a hydrogen atom, deuterium atom, Ci_ 2 o 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, (CH 2 ) n substituted phenyl, (CH 2 ) n (l- or 2- naphthyl), (CH 2 ) n heteroaryl, CH 2 N 2 N 2
  • 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), C0(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, (CH 2 ) n substituted phenyl, (CH 2 ) n (l- or 2- naphthyl), (CH 2 ) n heteroaryl, biotin, dinitrophenyl (DNP), iodoacetamides, DTNB, COR (ex. 2-quinolinylcarbonyl), COOR, C0(CH 2 ) n NH(Z), Acridine derivatives (Red, yellow, orange ....),
  • Fluorescein derivatives fluorescein, FITC, FAM (carboxyfluorescein), 5-(and-6)- carboxynaphtho fluorescein, carboxyfluorescein, BCECF, napto fluorescein ),
  • Oregon Green® (2',7'-difluorofluorescem) dyes (Oregon Green® 488, Oregon Green® 5147), BODIPY® (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a- diaza-s- indacene-3-propionic acid) dyes (BODIPY FL, BODIPY TMR, BODIPY TR,
  • AMC aminomethylcoumarin
  • AMCA aminocoumarin, diethylamino coumarin hydroxymethylcoumarin
  • AFC aminocoumarin, methoxycoumarin
  • Cyanin derivatives phycocyanin, allophycocyanin (APC), CY3.18, CY5.18, Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7
  • Erythrin/Phycoerythrin derivatives R-Phycoerythrin
  • PE B-Phycoerythrin
  • APC/PE-Cy conjugates PE-Cy5 conjugates, PE-Cy7 conjugates, APC-Cy7 conjugates....
  • Calcein derivatives calcein, SNAFL calcein....
  • DANS DANSA
  • Cascade Blue Lucifer yellow, NBD, Red 613, FluorX, Rhodamine derivatives(Rhodamine 123, Rhodamine 110, Rhodamine B, Rhodamine 6A, Rhodamine 6G, TRITC, X-Rhodamine, sulphorhodamin,
  • Rhodamine Red-X LissamineTM rhodamine B, DHR, Rhodamine Green....
  • PerCP Texas Red, TruRed, Alexa Fluo ® (Alexa Fluor 350, Alexa Fluor 430, 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 Fluor® 594, ZenonTM Alexa Fluor® 647, ZenonTM Allophycocyanin, ZenonTM Biotin-XX, ZenonTM R-
  • 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,
  • 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, thiomortholine, 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, in
  • R is a hydrogen atom, C 1-2 O aliphatic group, aryl, substituted aryl (ex: 4- nitrophenyl or coumarine derivatives), hetetoaryl (ex. 2-pyridine), substituted heteroaryl, cycloalkyl, naphthyl, substituted naphthyl, (CH 2 ) n cycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n substituted phenyl (ex: 2,6-dihalophenyl), (CH 2 ) n (l- or 2- naphthyl), (CH 2 ) n heteroaryl or (un)substituted (2-, 3-, 4-, 5-, 6-, 7- or 8-) quinolinyl, fluorenmethyl ;
  • Y is an electronegative leaving group including halogens such as F, Cl, Br or I, aryl or alkylsulfonyloxy groups, trifluoromethanesulfonyloxy, OR, SR, COOR, OP(O)R 2 wherein R is an aliphatic group, an aryl group, an alkyl group, a carbocyclic group, an alkyl carbocyclic group, or a heterocyclic group ;
  • (xii) Z is a halogen (F, Cl, Br or I), CN, OH, OR, NH 2 , NHR, NR 2 , SR, COR, CO 2 R, CONR 2 ;
  • 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-
  • R 1 , R 2 , R 3 ,R 4 ,R 5 ,R 6 and R 7 may include (but not restrictively) "cold labelling" in their structure including 13 C, 2 H, 15 N, 19 F, 31 P, 23 Na or 31 K
  • 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 poly cyclic 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-8 activity in in vitro or in vivo cell death.
  • said derivatives are used for in vivo inhibition of caspase-8 activity to provide cytoprotective effect.
  • they are used for in vitro inhibition of caspase-8 activity.
  • the invention also relates to the use of said derivatives as drugs. It is then an object of the invention to provide pharmaceutical 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 lenticulostriate 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, retinal
  • 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.
  • the invention also provides methods for using the above derivatives to inhibit caspase activity and to treat caspase-8-mediated disease states.
  • caspase activity assays were performed as following to determine the inhibitory profile of the derivative of formula (I) with SEQ ID N 0 1.25U of human (caspase-1 to -10 and -14; Biomol, Madison, Pennsylvania, USA).
  • Recombinant caspases were pre-incubated during 30 min at 37°C with the test compound (or not) in the assay buffer (50 mM HEPES, pH 7.4, 10OmM NaCl, 0.1% CHAPS, 10 mM DTT, ImM EDTA, 10% glycerol), and then mixed with 200 ⁇ M of the corresponding fluorogenic caspase substrates (Biomol , Sigma, St- Quentin Fallavier, France): Ac-YVAD-AMC (caspase-1, Cl), Ac-VDVAD-AMC (Caspase-2, C2), Ac-DEVD-AMC (caspase-3/7, C3 and C7), Ac-WEHD-AMC (caspase-4,-5,-11, -14;
  • An IC50 value corresponding to the concentration that could inhibit 50% of caspase activity can be 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.
  • SEQl was tested in vivo in a well established model reproducing fulminant liver hepatitis. To proceed, 5 mg/kg of SEQl (10% DMSO, 90% 0.9% NaCl) was intraperitonneally (ip) administred to C57bl6 mice (Charles River) 30 min before ip injection of JO2 (Pharmingen) Fas antibody (0.3 ⁇ g/g).
  • mice were sacrificed at 3 h post JO2 and ex vivo (TUNEL) staining was performed to estimate cell death.
  • SEQl prevent liver cell death (decrease of TUNEL staining by at least 68+/- 10%) and 4/5 mice have pronounced protection (more than 70%) (Figure 3).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Genetics & Genomics (AREA)
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Abstract

L'invention concerne de nouveaux inhibiteurs de caspase-8 sélectifs qui reconnaissent la caspase-8 et bloquent son activité fondée sur la SEQ1.
PCT/IB2008/055564 2007-12-27 2008-12-29 Inhibiteurs de caspase-8 et utilisations de ceux-ci WO2009083930A1 (fr)

Applications Claiming Priority (2)

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US914407P 2007-12-27 2007-12-27
US61/009,144 2007-12-27

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WO2009083930A1 true WO2009083930A1 (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
US20020086832A1 (en) * 1999-04-06 2002-07-04 Apotech Research And Development Ltd. Caspase inhibitors for inhibiting blood cell proliferation and for treating autoimmune diseases
US20070172489A1 (en) * 2003-03-26 2007-07-26 Stefan Ludwig Caspase inhibitors, especially caspase 3 inhibitors, for the treatment of influenza

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020086832A1 (en) * 1999-04-06 2002-07-04 Apotech Research And Development Ltd. Caspase inhibitors for inhibiting blood cell proliferation and for treating autoimmune diseases
US20070172489A1 (en) * 2003-03-26 2007-07-26 Stefan Ludwig Caspase inhibitors, especially caspase 3 inhibitors, for the treatment of influenza

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 1 April 2004 (2004-04-01), KO CHING HUAI ET AL: "Hydroxylation at C4' or C6 is essential for apoptosis-inducing activity of flavanone through activation of the caspase-3 cascade and production of reactive oxygen species.", XP002526463, Database accession no. NLM15019974 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 2003, ARAKI TAKASHI ET AL: "Caspase-9 takes part in programmed cell death in developing mouse kidney.", XP002526464, Database accession no. NLM12660414 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; November 2007 (2007-11-01), LI BING-HUA ET AL: "Polypeptide from Chlamys farreri inhibits UVB-induced HaCaT cells apoptosis via inhibition CD95 pathway and reactive oxygen species.", XP002526462, Database accession no. NLM17907002 *
FREE RADICAL BIOLOGY & MEDICINE 1 APR 2004, vol. 36, no. 7, 1 April 2004 (2004-04-01), pages 897 - 910, ISSN: 0891-5849 *
FREE RADICAL RESEARCH NOV 2007, vol. 41, no. 11, November 2007 (2007-11-01), pages 1224 - 1232, ISSN: 1071-5762 *
NEPHRON. EXPERIMENTAL NEPHROLOGY 2003, vol. 93, no. 3, 2003, pages e117 - e124, ISSN: 1660-2129 *

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