EP1755586A2 - Inhibiteurs de metalloproteines comprenant une hydroxypyridinone, une hydroxypyridinethione, une pyrone, et une thiopyrone - Google Patents

Inhibiteurs de metalloproteines comprenant une hydroxypyridinone, une hydroxypyridinethione, une pyrone, et une thiopyrone

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Publication number
EP1755586A2
EP1755586A2 EP05818191A EP05818191A EP1755586A2 EP 1755586 A2 EP1755586 A2 EP 1755586A2 EP 05818191 A EP05818191 A EP 05818191A EP 05818191 A EP05818191 A EP 05818191A EP 1755586 A2 EP1755586 A2 EP 1755586A2
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EP
European Patent Office
Prior art keywords
inhibitor
alkyl
metalloprotein
aryl
phenyl
Prior art date
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EP05818191A
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German (de)
English (en)
Inventor
David T. Puerta
Seth M. Cohen
Jana A. Lewis
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University of California
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University of California
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Priority claimed from PCT/US2005/009277 external-priority patent/WO2005110399A2/fr
Application filed by University of California filed Critical University of California
Publication of EP1755586A2 publication Critical patent/EP1755586A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • MMPs are a class of zinc(II) -containing hydrolytic enzymes involved in the breakdown of the extracellular matrix and the basement-membrane including components such as aggrecan, collagen, elastin, fibronectin, gelatin, and laminin.
  • the ability of MMPs to degrade components of the extracellular matrix is essential to tasks such as cell growth, cell division, bone growth, wound healing, embryogenesis, and angiogenesis.
  • 1 ' 2 Disruption of the regulation of MMP activity is correlated to disease states including but not limited to cardiovascular disease, stroke, arthritis, and tumor metastasis. 1"3 Many factors must be considered in designing an effective and selective drug.
  • MMPi matrix metal loproteinase inhibitors
  • the drug typically consists of two parts, a peptidomimetic backbone and a zinc-binding group (ZBG).
  • the backbone serves as a substrate analogue, allowing the inhibitor to fit in the active-site cleft of the enzyme.
  • the ZBG binds to the catalytic zinc(II) ion, thereby rendering the MMP inactive.
  • ZBG zinc-binding group
  • Histone deacetylases and the silent information regulator-like family of NAD-dependent deacetylases are important in transcriptional regulation. Acetylation neutralizes the lysine charge, and DNA unwinds, thus allowing active gene expression to occur. 4 Deacetylation leads to the packing of nucleosomes as chromatins and thus gene repression. HDACs deacetylate using an activated water in the active site where two glutamic acid residues and a histidine residue are coordinated to an active site metal ion with a histidine-aspartate charge-relay system. 5 Anomalous HDAC activity has been associated with cancer, and HDAC inhibitors have been proposed as cancer treatments. 6 With HDAC inhibitors
  • HDACi the drug generally has a form of a ZBG to bind the catalytic zinc ion, a linker to interact with the narrow channel leading down to the active site, and a surface recognition or capping group that will interact with the surface of the protein.
  • Some of the HDACi in the literature include short chain fatty acids like valproic acid, hydroxamates like trichostatin A, cyclic hydroxamic-acid-containing peptide compounds, epoxides, and benzamidines. 7 ' 8
  • Anthrax spores are taken up by alveolar macrophages and germinate in the lymphnodes where the spores create toxins to inhibit immune responses.
  • Anthrax is often asymptomatic until it reaches the blood, and then it is often fatal and non- responsive to traditional antibiotics.
  • the protective antigen (PA) In order for an anthrax infection to be toxic, the protective antigen (PA) must form a heptamer that will mediate entry of up to three molecules of edema factor (EF) and lethal factor (LF) per heptamer into cells.
  • Anthrax lethal factor is one of three proteins involved in anthrax pathogenesis and lethality. Inactivation of the LF gene in B.
  • anthracis leads to a thousand-fold or greater reduction of virulence, which suggests that anthrax pathology is largely determined by LF.
  • 11 LF cleaves the N-terminus of the D-domain of mitogen- activated protein kinase kinases (MAPKK), which impairs essential signal transduction pathways such as inhibiting the activation of p38 MAPK switching the signaling macrophage apoptosis before macrophages can be activated and spread the alarm of infection.
  • MAPKK mitogen- activated protein kinase kinases
  • the active site of anthrax lethal factor consists of two histidine residues and a glutamic acid residue bound to a zinc(II) ion.
  • LF inhibitors contain a hydroxamate as a ZBG
  • some proposed inhibitors are based on animoglycosides, small peptides attached to a ZBG, or were identified from the NCI Diversity Set. 12'14 Summary of the Invention
  • the present invention provides metalloprotein inhibitors (MPI), such as matrix metalloproteinase inhibitors (MMPi), histone deacetylase inhibitors (HDACi), or anthrax lethal factor inhibitors (LFi).
  • MMPi matrix metalloproteinase inhibitors
  • HDACi histone deacetylase inhibitors
  • LFi anthrax lethal factor inhibitors
  • the present invention provides a metalloprotein inhibitor, of formula (I):
  • R 1 , R 2 , R 3 , and R 4 are individually hydrogen or another substituent, wherein at least one of R 1 , R 2 , R 3 and R 4 is an organic substituent, or a pharmaceutically acceptable salt thereof.
  • at least two of R 1 , R 2 , R 3 and R 4 is an organic substituent.
  • the present invention provides a metalloprotein inhibitor comprising: an organic substituent and two or more zinc binding groups (ZBG) covalently attached thereto, wherein the ZBG is of formula (II):
  • R 1 , R 2 , R 3 , and R 4 are individually hydrogen or another substituent, or a pharmaceutically acceptable salt thereof.
  • at least one of R 1 , R 2 , R 3 and R 4 is an organic substituent.
  • At least one of R 1 , R 2 , R 3 or R 4 comprises one or more amido and/or amino moieties, including one or more peptidyl residues.
  • at least one of R 1 , R 2 , R 3 or R 4 can be a naturally- occurring peptide, a synthetic peptide, or a peptide analog (peptidomimetic), e.g., that comprises one or more amido moieties (-C(O)NH-).
  • Specific embodiments of the invention include compounds, wherein one or two ofR 1 , R 2 , R 3 or R 4 is [[(C 6 -C 10 )aryl] q -[O] p -[(C 6 -C, 0 )aryl]-[O] r -[(C,-C 6 )alkyl] o - [C(O)] s -[N(R)]-[C(O)],-[(C,-C 6 )alkyl] w -] (III) wherein q, p, r, o, s, t and w are individually is 0 or 1 and R is H, (Ci-C4)alkyl, phenyl, or benzyl.
  • (C 6 -Ci 0 )aryl is phenyl, preferably 1,4-phenylene; preferably p, r, o, and w are 0 and s is 1 ; preferably t is 1 ; preferably t is 1 and w or o is 1, most preferably -CH 2 -, -(CH 2 ) 2 - or ⁇ -(CH 2 ) 3 -; preferably p is 0, r is 0, o is -CH 2 - or 0, s is 0, t is 1 and w is 0; preferably q, p, r, and t or s are 0; preferably q is 1, p is 1, o is 0, s is 0, t is 1 and w is 0; preferably q is 0 or 1, p is 0 or 1, r is 0, o is 1, s is 0, t is 0 and w is 1 ; and preferably q is 0 or 1, p is 0 or 1, r is 0,
  • R is H or -CH 3 -.
  • one of R 1 , R 2 , R 3 or R 4 is substituent (III); for example, one or two of R 1 , R 2 , R 3 or R 4 are individually biphenylcarbamyl, biphenylcarbamyl(Ci- C 6 )alkyl, biphenyl(Ci-C 6 )alkylcarbamyl, biphenyl(Ci-C 6 )alkylcarbamyl (Ci- C 6 )alkyl, phenoxyphenylcarbamyl, (C 6 -C] 0 )aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, biphenyl(C i -C ⁇ )alkylamino(C i -C 6 )alkyl, (C 6 -Ci o)arylcarbonylamino(C i -C 6 )alkyl, (C 6 -C
  • the invention also provides a pharmaceutical composition, such as a unit dosage form, comprising a metalloprotein inhibitor (MPI) compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, that can optionally include stabilizers, preservatives, buffers, and absorption control agents.
  • a pharmaceutical composition such as a unit dosage form, comprising a metalloprotein inhibitor (MPI) compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, that can optionally include stabilizers, preservatives, buffers, and absorption control agents.
  • MPI metalloprotein inhibitor
  • the invention provides a therapeutic method for preventing or treating a pathology, condition or symptom in a mammal, such as a human, that is associated with pathological metalloprotein activity, such as a matrix metalloproteinase (MMP), histone deacetylase (HDAC) or anthrax lethal factor (LF) activity that is alleviated by inhibition of said activity, comprising administering to a mammal in need of such therapy, an effective amount of a metalloprotein inhibitor (MPI) of the invention, including a pharmaceutically acceptable salt thereof.
  • MMPI matrix metalloproteinase
  • HDAC histone deacetylase
  • LF anthrax lethal factor
  • a method of preparing a metalloprotein inhibitor (MPI), by covalently attaching a ZBG of formula (II) to one or more backbone molecules is also within the scope of the invention.
  • MPIs of the invention can be used as intermediates to prepare other MPIs of the invention.
  • FIG. 1 Representative zinc-binding groups (ZBGs) (1-11). Acetohydroxamic acid (AHA) shown as reference.
  • Figure 2 A Chemical (top) and 2B structural (bottom, 50% probability ellipsoids) diagram of [(Tp ph>Me )Zn(9)] showing the chelation of the O,S ligand to the zinc(II) ion. Hydrogen atoms have been omitted for clarity.
  • Figure 4. Summary table of IC 50 values (uM) for novel ZBGs against MMP- 1, -2, and -3 measured using either a fluorescence- or colorimetric-based assay.
  • Figure 5. Raw data from fluorescent assay of 11 with MMP-3. Relative fluorescent units (RFU) produced from substrate cleavage in each reaction well: control (0 mM 11, circles •), 11 0.05 mM (squares ⁇ ), 11 0.1 mM (triangles A), 11 0.2 mM (diamonds ⁇ ), 11 0.3 mM (*), 11 0.5 mM (o), and 11 1.0 mM (x) are plotted versus time in minutes
  • Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals.
  • Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
  • Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells.
  • a major class of enzymes involved in this function is the MMPs.
  • MMPs are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-I, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP- 12, HME, human macrophage elastase) and membrane MMP (MMP-
  • Histones form the protein core of nucleosomes, which are DNA/protein complexes that are the subunits of eukaryotic chromatin.
  • the histones are subject to a variety of post-translational modifications such as phosphorylation, ubiquitination and acetylation. These modifications have profound regulatory functions in gene transcription.
  • the packing and unpacking of nucelosomes as chromatins regulates gene expression. Acetylation of histones leads to an open chromatin structure and gene activation while the deacetylation of histones leads to a condensed chromatin structure and gene repression. The loss of this balance for whatever reason leads to a number of disease states.
  • HDAC histone deacetylase
  • NAD + -dependent sometimes referred to as sirutins.
  • Examples are: HDACl, HDAC4, HDAC6, HDACl 1.
  • Anthrax lethal toxin which is a combination of anthrax lethal factor and anthrax protective antigen, impairs multiple systems in the host including human beings and other mammals.
  • Inactivation of the mitogen activated protein kinase (MAPK) signaling pathway in macrophages and dendritic cells impairs innate and adaptive immunity.
  • MAPK mitogen activated protein kinase
  • This disruption of the MAPK pathway has many consequences for the host including but not limited to suppression of cytokine secretion, downregulation of costimulatory molecules, defective T and B cell priming, impaired p38 phosphorylation, endothelial cell apoptosis, macrophage apoptosis and suppression of inflammation.
  • Anthrax lethal factor is involved in the effects of anthrax infection and the effects of anthrax lethal toxin.
  • the organic substituent(s) do(es) not substantially interfere with the ability of the moiety
  • the organic radical(s) enhance(s) the ability of said moieties to bind to said Zn(II), or other metal ions.
  • R 1 , R 2 , R 3 and R 4 are less bulky than the primary organic substituent(s), although 1-2 of R 1 , R 2 , or R 3 can be a second or third organic substituent in some instances.
  • R 1 , R 2 , R 3 , and R 4 are individually H, halo, CN, nitro, carboxyl, amino, sulfonamido, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (C 3 - C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl((C,-C 6 )alkyl), (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 2 - C )0 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(C r C 6 )al
  • one of R 3 or R 4 is [[(C 6 -Ci 0 )aryl] q -[0] q -[(C 6 -Cio)aryl]- [O] q -[(C,-C 6 )alkyl] q -[C(O)] q -[N(R)]-[C(O)] q -[(C,-C6)alkyl] q -] wherein q is 0-1 and R is H, (Ci-C 4 )alkyl, phenyl, or benzyl.
  • one of R 3 or R 4 is [[(C 6 -Ci 0 )aryl] q -[O] q -[(C 6 - C 10 )aryl]-[O] q -[(C 1 -C 6 )alkyl] q -[C(O)] q -[N(R)]-[C(O)] q -[(C 1 -C 6 )alkyl] q -] wherein q is 0-1 and R is H, (Ci-C 4 )alkyl, phenyl, or benzyl, and the ZBG is
  • R 3 and R 4 are side chains that are individually biphenylcarbamyl, biphenylcarbamyl- (C r C 6 )alkyl, biphenyl(Ci-C 6 )alkylcarbamyl, biphenyl(Ci-C 6 )alkylcarbamyl (Ci-C 6 )alkyl, phenoxyphenylcarbamyl, (C 6 - C 1 0 )aryl(C i -C 6 )alkylamino(C i -C 6 )alkyl, biphenyl(C i -C 6 )alkylamino(C i -C 6 )alkyl, (C 6 -C i o)arylcarbonylamino(C i -C 6 )alkyl, (C 6 -C 10 )aryl(C i - C 6 )alkylcarbonylamino(C i -C 6 )alkyl, (
  • Exemplary side chains include biphenylmethylcarbamyl, phenoxyphenylcarbamyl, biphenylcarbamyl, benzylaminomethyl, phenethylaminomethyl, benzoylaminomethyl, benzylcarbonylaminomethyl, phenethylcarbonylaminomethyl, phenylpropylcarbonylaminomethyl, biphenylmethylcarbamylmethyl, phenoxyphenylcarbamylmethyl, biphenylcarbamylmethyl, and biphenylyloxyethylcarbonylaminomethyl, wherein the phenyl groups are optionally substituted with one to four R 1 .
  • MPI compounds comprising ZBGs of formula (II) wherein the dangling valence is substituted by R 7 , wherein R 7 is selected from R 1 , R 2 , or R 3 .
  • R 7 can also be a polymer chain, such as a polyanhydride, polylactone, polyether, polyester, polyamide, polyalkenylene, polyol, and the like.
  • the term "treatment" of a metalloprotein-associated pathology includes inhibiting metalloprotein activity such as HDAC, LF, or MMP activity in a subject exhibiting at least one of the symptoms of the onset of a metalloprotein-associated pathology or who is likely to develop such a pathology as well as the ability to halt or slow the progression of a metalloprotein-associated pathology or to reduce or alleviate at least one of the symptoms of said pathology.
  • a “therapeutic effect”, “effective amount,” or “therapeutic effective amount” is intended to qualify the amount of an anticancer agent according to the present invention required to relieve to some extent one or more of the symptoms and/or conditions of cancer, including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 4) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 5) inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or more of the symptoms associated with cancer; and/or 7) relieving or reducing the side effects associated with the administration of anticancer agents.
  • the terms also are intended to qualify the amounts of anti-inflammatory agents or anti-anthrax lethal factor agents according to the present invention required to relieve to some extent one or more of the symptoms and/or conditions of diseases including, but not limited to arthritis (e.g., RA), restenosis, aortic aneurism, IBD, glomerular nephritis, MS, stroke, diabetes, bacterial meningitis, and graft vs. host disease.
  • the terms also are intended to qualify the amounts of agents according to the present invention required to relieve to some extent one or more of the symptoms and/or conditions of diseases include epidermal scars, myocardial infarction, and periodontal disease.
  • the use of the term "about" in the present disclosure means
  • MMPI metaloprotein inhibitor
  • HDAC histone deacetylase
  • LF fatty acid deacetylase
  • MMPs are involved in the degradation of connective tissue or connective tissue components. These enzymes are released from resident tissue cells and/or invading inflammatory or tumor cells. Blocking the action of MMPs interferes with the creation of paths for newly forming blood vessels to follow. Examples of MMPi are described in Whittaker et al. and is hereby incorporated by reference. 1
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho- fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing about 5 or 6 ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(R 7 ) wherein R 7 is absent or is as defined above; as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • (C r C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -C i 2 )cycloalkyl can be monocyclic, bicyclic or tricyclic and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octanyl, norbornyl, adamantyl as well as various terpene and terpenoid structures.
  • (C 3 -C i 2 )cycloalkyl(Ci-C ⁇ )alkyl includes the foregoing cycloalkyl and can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2- cyclohexylethyl.
  • Heterocycloalkyl and (heterocycloalkyl)alkyl include the foregoing cycloalkyl wherein the cycloalkyl ring system is monocyclic, bicyclic or tricyclic and optionally comprises 1-2 S, non-peroxide O or N(R 7 ) as well as 2-12 ring carbon atoms; such as morpholinyl, piperidinyl, piperazinyl, indanyl, 1,3- dithian-2-yl, and the like; the cycloalkyl ring system optionally includes 1-3 double bonds or epoxy moieties and optionally is substituted with 1-3 OH, (Ci- C 6 )alkanoyloxy, (CO), (C,-C 6 )alkyl or (C 2 -C 6 )alkynyl.
  • the cycloalkyl ring system is monocyclic, bicyclic or tricyclic and optionally comprises 1-2 S, non-peroxide O or N(R 7 )
  • (Ci-C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3- pentoxy, or hexyloxy
  • (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl
  • (C 2 -C 6 )alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pent
  • any of R 1 , R 2 , or R 3 can be substituted by one to three R 1 (except for H, halo or CN).
  • one of R 1 , R 2 , or R 3 is (C,-C 3 )alkyl.
  • one of R 1 , R 2 , or R 3 is H.
  • R 4 is (Ci-Qs)alkyl, benzyl, t-Boc, (C 3 -C 6 )cycloalkyl(Ci-C 3 )alkyl, or H.
  • Useful backbone molecules comprise organic substituents having the structural features depicted in Fig. 5 and Fig. 6 of Whittaker et al., 1 wherein the moiety HON(H)-C(O)-CH(R a )- has been replaced with a ZBG of formula (I), or the structural features depicted in the claims of EPA 126,974, wherein at least the moiety COR 1 has been replaced by a ZBG of formula (I).
  • the structure of the organic backbone molecule(s) and other organic substituents preferably do not interfere with and, preferably enhance the ability of the MPI to direct the ZBG toward one or more complexed metal ions, such as Zn(II) atoms of the MMP.
  • Pep can be any of the organic radicals derived from the structures shown on Scheme 1 of the Whittaker et. al., 1 after removal of the C(O)NH(OH) group, or in the claims of published European patent application No. 126,974, after removal of COR 1 .
  • the organic backbone molecule and/or organic substituent(s) can be a naturally-occurring peptide, a synthetic peptide or a peptide analog (peptidomimetic).
  • Such groups may comprise one or more amido moieties (-C(O)NH-), which can be or comprise, peptidyl bonds, e.g., amide bonds formed by reaction of the amino group of an ⁇ /p ⁇ -aminocarboxylic acid with the carboxy group of a second amino acid.
  • amido moieties -C(O)NH-
  • peptidyl bonds e.g., amide bonds formed by reaction of the amino group of an ⁇ /p ⁇ -aminocarboxylic acid with the carboxy group of a second amino acid.
  • embodiments of the compound of formula (I) or (II) can be represented by [ZBG]-C(R 5 )(R 6 )-C(O)NH-, [ZBG]-C(R 8 )-C(O)N(H)-CH(R 9 )- C(O)NH(R 10 ), or [ZBG-C(R 5 )(R 6 )-C(O)N(H)-CH(R 9 )-C(O)NH(R 10 ), wherein ZBG comprises the heterocyclic ring of formula (I) or (II) R 8 , R 9 and R 10 correspond to R 1 , R 2 and R 3 respectively, and wherein R 5 is H and R 6 is (Ci-C 22 )alkyl, (C 2 - C 6 )alkenyl, (C 6 -Ci 0 )aryl, (C,-C 6 )alkyl, (C 6 -C io)heteroaryl, (C 6 -C
  • peptidyl or peptidomimetic substituents are terminated by a ZBG of formula (I) or (II), and optionally, the other terminus is C(O)N(R 6 )(R 7 ).
  • compositions are sufficiently basic or acidic to form stable nontoxic acid or base salts
  • administration of the compounds as salts may be appropriate.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Pharmaceutically acceptable salts include metallic ions and organic ions.
  • More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, for example, sodium potassium, or lithium, and alkaline earth metal (Group Ha) salts, for example, calcium, and other physiological acceptable metal ions.
  • Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.
  • Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Illustrative pharmaceutically acceptable salts are prepared from hydrochloric, hydrobromic, phosphoric, sulfuric, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, ⁇ -hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxy- ethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, /5-hydroxybutyric, galactaric and galacturonic acids.
  • compositions of the present invention are usually administered in the form of pharmaceutical compositions.
  • These compositions can be administered by any appropriate route including, but not limited to, oral, nasogastric, rectal, transdermal, parenteral (for example, subcutaneous, intramuscular, intravenous, intramedullary, intrasternal, and intradermal injections, or infusion techniques), intranasal, transmucosal, implantation, vaginal, topical, buccal, and sublingual administration.
  • Such preparations may routinely contain buffering agents, preservatives, penetration enhancers, compatible carriers, and other therapeutic or non-therapeutic ingredients.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable dilutent or solvent, for example, as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration can include capsules, ingestible tablets, buccal tablets, troches, dragees, pills, powders, granules, and wafers.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • tablets, pills, granules, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • the tablets, pills, granules, or capsules comprising the inventive compositions may be film coated or enteric-coated.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like.
  • Useful liquid carriers include water, alcohols or glycols, or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
  • the present invention also includes methods employing a pharmaceutical composition that contains the composition of the present invention associated with pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipients” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for ingestible substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compositions, its use is contemplated.
  • compositions(s) can be mixed with a pharmaceutically acceptable excipient, diluted by the excipient or enclosed within such a carrier, which can be in the form of a capsule, sachet, or other container.
  • a pharmaceutically acceptable excipient diluted by the excipient or enclosed within such a carrier, which can be in the form of a capsule, sachet, or other container.
  • the carrier materials that can be employed in making the composition of the present invention are any of those commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with the active drug and the release profile properties of the desired dosage form.
  • binders such as acacia, alginic acid and salts thereof, cellulose derivatives, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, polyethylene glycol, gums, polysaccharide acids, bentonites, hydroxypropyl methylcellulose, gelatin, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, pregelatinized starch, ethylcellulose, tragacanth, dextrin, microcrystalline cellulose, sucrose, or glucose, and the like.
  • Binders such as acacia, alginic acid and salts thereof, cellulose derivatives, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, polyethylene glycol, gums, polysaccharide acids
  • Disintegration agents such as starches, pregelatinized corn starch, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, sodium starch glycolate, crospovidone, cross-linked polyvinylpyrrolidone, croscarmellose sodium, microcrystalline cellulose, a calcium, a sodium alginate complex, clays, alginates, gums, or sodium starch glycolate, and any disintegration agents used in tablet preparations.
  • (c) Filling agents such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, PluronicTM line (BASF), and the like.
  • Solubilizer such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate and sodium carbonate and the like.
  • Stabilizers such as any antioxidation agents, buffers, or acids, and the like, can also be utilized.
  • Lubricants such as magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl behapate, magnesium, calcium and sodium stearates, stearic acid, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, or sodium lauryl sulfate, and the like.
  • Lubricants such as magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl behapate, magnesium, calcium and sodium stearates, stearic acid, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, or sodium la
  • wetting agents such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, or sodium lauryl sulfate, and the like.
  • Diluents such lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, or bentonite, and the like.
  • Anti-adherents or glidants such as talc, corn starch, DL-leucine, sodium lauryl sulfate, and magnesium, calcium, or sodium stearates, and the like.
  • Pharmaceutically compatible carrier comprises acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, or pregelatinized starch, and the like.
  • Mammal includes a primate, for example, a monkey, or a lemur, a horse, a dog, a pig, or a cat.
  • a rodent includes a rat, a mouse, a squirrel, or a guinea pig.
  • the invention provides a therapeutic method for preventing or treating a pathological disease, condition or symptom in a mammal, such as a human, that is associated with pathological metalloprotein activity, such as a matrix metalloproteinase (MMP), histone deacetylase (HDAC) or anthrax lethal factor (LF) activity that is alleviated by inhibition of said activity, comprising administering to a mammal in need of such therapy, an effective amount of a metalloprotein inhibitor (MPI) of the invention, including a pharmaceutically acceptable salt thereof.
  • MMP matrix metalloproteinase
  • HDAC histone deacetylase
  • LF anthrax lethal factor
  • MPI metalloprotein inhibitor
  • Such conditions, disease or symptoms include cancer, anthrax pathogenesis associated with anthrax lethal factor, and the inflammatory pathologies set forth in Whitaker, et al.
  • cancers amenable to treatment include leukemia, myeloma, lymphoma, metastatic breast or metastatic prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, osteosarcoma, germ cell tumor, lung cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, melanoma, myelodysplastic syndrome, Ewing's sarcoma, and Paget's disease.
  • Other conditions or diseases amenable to treatment include epidermal scars, myocardial infarction, and periodontal disease.
  • compositions of the invention can be used to provide a dose of a compound of the present invention in an amount sufficient to elicit a therapeutic response, e.g., inhibition of tumor growth, for example a dose of about 5 ng to about 1000 mg, or about 100 ng to about 600 mg, or about 1 mg to about 500 mg, or about 20 mg to about 400 mg.
  • a dosage effective amount will range from about 0.0001 mg/kg to 1500 mg/kg, more preferably 1 to 1000 mg/kg, more preferably from about 1 to 150 mg/kg of body weight, and most preferably about 50 to 100 mg/kg of body weight.
  • a dose can be administered in one to about four doses per day, or in as many doses per day to elicit a therapeutic effect.
  • a dosage unit of a composition of the present invention can typically contain, for example, about 5 ng, 50 ng 100 ng, 500 ng, 1 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of a compound of the present invention.
  • the dosage form can be selected to accommodate the desired frequency of administration used to achieve the specified dosage.
  • the amount of the unit dosage form of the composition that is administered and the dosage regimen for treating the condition or disorder depends on a variety of factors, including, the age, weight, sex and medical condition, of the subject, the severity of the condition or disorder, the route and frequency of administration, and this can vary widely, as is well known.
  • the composition is administered to a subject in an effective amount, that is, the composition is administered in an amount that achieves a therapeutically effective dose of a compound of the present invention in the blood serum of a subject for a period of time to elicit a desired therapeutic effect.
  • the composition in a fasting adult human (fasting for generally at least 10 hours) the composition is administered to achieve a therapeutically effective dose of a compound of the present invention in the blood serum of a subject from about 5 minutes after administration of the composition.
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 10 minutes from the time of administration of the composition to the subject.
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 20 minutes from the time of administration of the composition to the subject. In yet another embodiment of the present invention, a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 30 minutes from the time of administration of the composition to the subject. In still another embodiment of the present invention, a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 40 minutes from the time of administration of the composition to the subject.
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 20 minutes to about 12 hours from the time of administration of the composition to the subject
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 20 minutes to about 6 hours from the time of administration of the composition to the subject
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 20 minutes to about 2 hours from the time of administration of the composition to the subject
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 40 minutes to about 2 hours from the time of administration of the composition to the subject.
  • a therapeutically effective dose of the compound of the present invention is achieved in the blood serum of a subject at about 40 minutes to about 1 hour from the time of administration of the composition
  • a composition of the present invention is administered at a dose suitable to provide a blood serum concentration with a half maximum dose of a compound of the present invention.
  • a blood serum concentration of about 0.01 to about 1000 nM, or about 0.1 to about 750 nM, or about 1 to about 500 nM, or about 20 to about 1000 nM, or about 100 to about 500 nM, or about 200 to about 400 nM is achieved in a subject after administration of a composition of the present invention.
  • compositions of the present invention provide a therapeutic effect as compound of the present invention medications over an interval of about 5 minutes to about 24 hours after administration, enabling once-a-day or twice-a-day administration if desired.
  • the composition is administered at a dose suitable to provide an average blood serum concentration with a half maximum dose of a compound of the present invention of at least about 1 ⁇ g/ml, or at least about 5 ⁇ g/ml, or at least about 10 ⁇ g/ml, or at least about 50 ⁇ g/ml, or at least about 100 ⁇ g/ml, or at least about 500 ⁇ g/ml, or at least about 1000 ⁇ g/ml in a subject about 10, 20, 30, or 40 minutes after administration of the composition to the subject.
  • the amount of therapeutic agent necessary to elicit a therapeutic effect can be experimentally determined based on, for example, the absorption rate of the agent into the blood serum, the bioavailability of the agent, and the potency for treating the disorder. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular subject depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject (including, for example, whether the subject is in a fasting or fed state), the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy.
  • dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for subject administration.
  • Studies in animal models generally may be used for guidance regarding effective dosages for treatment of diseases in accordance with the present invention.
  • the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular subject, etc.
  • a compound is found to demonstrate in vitro activity at, for example, a half-maximum effective dose of 200 nM
  • administer an amount of the drug that is effective to provide about a half- maximum effective dose of 200 nM concentration in vivo for a period of time that elicits a desired therapeutic effect, for example, treating a disorder related to high beta-amyloid-induced neurotoxicity and other indicators as are selected as appropriate measures by those skilled in the art. Determination of these parameters is well within the skill of the art. These considerations are well known in the art and are described in standard textbooks.
  • serum concentrations of a compound of the present invention can be measured using standard assay techniques.
  • compositions of the present invention provide a therapeutic effect over an interval of about 30 minutes to about 24 hours after administration to a subject. In one embodiment compositions provide such therapeutic effect in about 30 minutes. In another embodiment compositions provide therapeutic effect over about 24 hours, enabling once-a-day administration to improve patient compliance.
  • compositions can also be used in combination ("combination therapy") with another pharmaceutical agent that is indicated for treating cancer, anthrax pathogenesis associated with anthrax lethal factor, and the inflammatory pathologies and other conditions or diseases set forth above.
  • Tris(pyrazolv ⁇ borate Model Complexes Previous work has shown that tris(pyrazolyl)borate complexes of zinc provide an accurate model for the tris(histidine) active site of several metalloproteins including MMPs. 16"20 In addition, studies on these model compounds have shown that acetohydroxamic acid forms a complex that is structurally identical to the coordination environment of hydroxamate-based drugs bound to the catalytic zinc(II) ion in MMPs. 16 ' 21 Using this same model, the interaction of ZBGs from identified inhibitors was evaluated where the mode of binding was unknown. 16 This study proved to be very informative, because a direct correlation between the inhibitory activity and mode of binding was found. 10 These observations further validate the use of model complexes as an effective strategy for determining, at a molecular level, the interactions between inhibitors and MMPs.
  • Tris(pyrazolyl)borate complexes of zinc(II) can be used as an initial screen for ZBGs by providing structural and qualitative binding information without the need for sophisticated drug synthesis or protein structure determination.
  • the structures show ( Figure 2 shows a representative example) that all of the novel ZBGs in Figure 1 can coordinate the zinc(II) ion in a bidentate fashion. * The metal-ligand bond lengths are compared to those found in the corresponding acetohydroxamate complex. 10 These model-based studies further support the invention described here and are believed to provide additional characterization for the mode of action of these metal chelators toward metal loproteins and MPI design.
  • Kojic Amine Kojic Azide (325mg 1.94mmol) was dissolved in 10OmL EtOH. To this solution was added Lindlar catalyst. The azide was hydrogenated at 35psi for 1 hour at room temperature. Filtered off catalyst and rotovapped to light brown slolid. Dissolved in hot water and filtered off insolubles. Rotovapped filtrate to a white-tan solid 250mg (91%).
  • KA2 The same procedure was used as in the synthesis of KAl.
  • the catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH 2 Cl 2 and MeOH. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU and recrystallized from EtOH to yield a white, feathery microcrystalline solid. Yield: 31%.
  • the catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH 2 Cl 2 and MeOH and THF. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU to yield a white, feathery microcrystalline solid. Yield: 57%.
  • the catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 100 mL hot CH 2 Cl 2 .
  • An additional batch of product was isolated by cooling the EtOH filtrate to 0 0 C for 2 h.
  • the clear solution was concentrated by rotary evaporation to yield a white solid.
  • the solid was washed with MeOH to remove residual DCU. Yield: 22%.
  • protecting group it may be desirable optionally to use a protecting group during all or portions bove described synthetic procedures.
  • Such protecting groups and methods introduction and removal are well known in the art. See Greene, T.W.; Wutz, P.G.M. "Protecting Groups In Organic Synthesis” second edition, 1991, New York, John Wiley & Sons, Inc.
  • New chelators were selected that were expected to bind as well as or better than hydroxamates. Hydroxypyridinones (HOPOs) were selected as lead compounds for several reasons. HOPOs are known to be strong metal chelators. 27 ' 28 In addition, the cyclic structure of hydroxypyridinones reduces the degrees of freedom in the ligand, preventing the cis to trans isomerization that can occur in hydroxamic acids, which ultimately detracts from the thermodynamic affinity of the metal-ligand interaction. The basicity of hydroxypyridinones varies between isomers, which potentially allows for tuning the protonation state of the ligand to accommodate possible hydrogen-bonding interactions in the protein active site.
  • Sulfur-Containing MPIs Sulfur-containing ligands may be very good ZBGs because of the apparent thiophilicity of zinc(II). 31 ' 32 Similarly, other thiol-based MPIs have been studied and have shown reasonably good activity when compared to hydroxamate-based inhibitors. 1 ' 16 ' 33 ' 34 Combining the best features of both hydroxamates and thiol inhibitors into a single ZBG, sulfur-containing ZBGs were developed because of the higher affinity of sulfur for the Zn 2+ ion compared to oxygen.
  • ZBGs with rigid ring structures that lock the O,S-donor atoms in a cis conformation can bind Zn 2+ ion in a bidentate fashion, to minimize oxidation and disulfide bond formation, which can be problems for thiol MPI, in biological systems.
  • Figure 1 discloses the sulfur-containing molecules which were evaluated as ZBGs for MPI.
  • the IC 50 values were determine by a linear fit as per the assay kit instructions (Biomol, Inc.). In order to confirm the values obtained fluorescence-based assays, additional experiments were performed on some ZBGs using a widely-used colorimetric-based assay. 38 The IC 5O values from the colorimetric assays ( Figure 4) are in good agreement with those obtained by fluorescence measurements.
  • the IC 5 o value for inhibitors comprising at least one organic substituent were measured.
  • the IC 50 value was 240 nM for MMP-3.
  • Additional representative IC 50 values for MMP-3 inhibition include AM3: 90 ⁇ M; KA2: 200 ⁇ M; KA3: 930 ⁇ M; TKA3: 90 ⁇ M; KA4: 400 ⁇ M; and CAl: 25% inhibition @ 50 ⁇ M.
  • potent and selective metalloprotein inhibitors such as matrix metalloproteinase inhibitors presents the possibility to treat many diseases, including those disclosed in Refs. 1-3, incorporated by reference herein.
  • the ZBGs shown in Figure 1 can readily be elaborated by adding a wide variety of substituents to the open ring positions, particularly peptidomimetic backbones, such as those shown in Reference 1 and in EPA 126,974.

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Abstract

L'invention concerne des inhibiteurs de métalloprotéines comprenant : a) un substituant organique et au moins un groupe de liaison au zinc (ZBG) lié par covalence à celui-ci, ou, b) un ZBG substitué par une chaîne latérale, où le ZBG est de formule (I), dans laquelle X désigne un O ou un S, et chaque R1, R2, R3, et R4 désigne, individuellement, un hydrogène ou un radical organique. Les inhibiteurs de métalloprotéines sont utilisés pour la prévention ou le traitement d'une maladie, état ou symptôme pathologique associé à une activité métalloprotéinique pathologique et/ou atténué par inhibition de ladite activité.
EP05818191A 2004-04-29 2005-04-28 Inhibiteurs de metalloproteines comprenant une hydroxypyridinone, une hydroxypyridinethione, une pyrone, et une thiopyrone Withdrawn EP1755586A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US56688204P 2004-04-29 2004-04-29
US57644404P 2004-06-03 2004-06-03
PCT/US2005/009277 WO2005110399A2 (fr) 2004-04-29 2005-03-21 Groupes de liaison au zinc pour inhibiteurs de metalloproteines
PCT/US2005/014747 WO2006028523A2 (fr) 2004-04-29 2005-04-28 Inhibiteurs de metalloproteines comprenant une hydroxypyridinone, une hydroxypyridinethione, une pyrone, et une thiopyrone

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US10982136B2 (en) 2016-02-26 2021-04-20 The Regents Of The University Of California Ligand-sensitized lanthanide nanocrystals as ultraviolet downconverters
US11684614B2 (en) 2016-09-06 2023-06-27 The Regents Of The University Of California Formulations of hydroxypyridonate actinide/lanthanide decorporation agents
US12002595B2 (en) 2016-09-29 2024-06-04 The Regents Of The University Of California Separation of metal ions by liquid-liquid extraction

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US10982136B2 (en) 2016-02-26 2021-04-20 The Regents Of The University Of California Ligand-sensitized lanthanide nanocrystals as ultraviolet downconverters
US11684614B2 (en) 2016-09-06 2023-06-27 The Regents Of The University Of California Formulations of hydroxypyridonate actinide/lanthanide decorporation agents
US12002595B2 (en) 2016-09-29 2024-06-04 The Regents Of The University Of California Separation of metal ions by liquid-liquid extraction

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