WO2015188060A1 - Inhibiteurs de seh substitués par fluorosulfonyle - Google Patents

Inhibiteurs de seh substitués par fluorosulfonyle Download PDF

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Publication number
WO2015188060A1
WO2015188060A1 PCT/US2015/034404 US2015034404W WO2015188060A1 WO 2015188060 A1 WO2015188060 A1 WO 2015188060A1 US 2015034404 W US2015034404 W US 2015034404W WO 2015188060 A1 WO2015188060 A1 WO 2015188060A1
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compound
nhc
group
seh
alkyl
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PCT/US2015/034404
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English (en)
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Jiajia Dong
Larisa KRASNOVA
K. Barry Sharpless
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The Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/26—Halogenosulfates, i.e. monoesters of halogenosulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/78—Halides of sulfonic acids
    • C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/88—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof

Definitions

  • This invention relates to soluble epoxide hydrolase inhibitors. More particularly, this invention relates to soluble epoxide hydrolase inhibitors provided with a
  • fluorosulfonyl-type group attached to a carbon, oxygen or nitrogen on the inhibitor structure.
  • Soluble epoxide hydrolase is a bifunctional, homodimeric enzyme with hydrolase and phosphatase activity, sEH is highly expressed in the liver, but it is also expressed in tissues such as vascular endothelium, leukocytes, red blood cells, smooth muscle cells, adipocytes, as well as the kidney proximal tubule. sEH metabolizes cis-epoxyeicosatrienoic acids (EETs) as well as other lipid mediators, and as such sEH plays a role in several diseases including hypertension, cardiac hypertrophy,
  • EETs cis-epoxyeicosatrienoic acids
  • arteriosclerosis brain and heart ischemia injury, cancer and pain.
  • Fluorosulfonyl derivatives of soluble epoxide hydrolase (sEH) inhibitors are useful for treatment of sEH-mediated diseases or conditions.
  • Fluorosulfonylated sEH compounds are represented by Formula (I):
  • R'-P'-L'-f P ⁇ L ⁇ P ⁇ wherein R 1 is selected from the group consisting of alkyl, heteroalkyl, C5-C 12 cycloalkyl, C5-C12 cycloalkylalkyl, C5-C12 cycloalkylheteroalkyl, arylalkyl, arylheteroalkyl, aryl, and heteroaryl; and R 1 can be substituted or unsubstituted; P 1 is a primary pharmacophore as further defined hereinbelow; P 2 is a secondary pharmacophore as further defined hereinbelow; P 3 is a tertiary pharmacophore as further defined hereinbelow; L 1 and L 2 are linking groups, also further defined herein; m has a value of 0 or 1 ; n has a value of 0 or 1 ; and the compound of Formula (I) includes at least one S0 2 F (“fluorosulfonyl”) group
  • R 3 can be substituted or unsubstituted and is selected from the group consisting of hydrogen, C
  • R 3 can be substituted or unsubstituted and is selected from the group consisting of hydrogen, C
  • fluorosulfonyl derivatives of sEH inhibitors possess anti-inflammatory, antiatherosclerotic, antihypertensive, and/or analgesic properties and can be administered to a patient in need of treatment as therapeutic agents orally, parenterally, subcutaneously, intramuscularly, intravenously or topically.
  • EETs trans-Epoxyeicosatrienoic acids
  • Epoxide hydrolases enzymes in the alpha/beta hydrolase fold family that add water to 3 membered cyclic ethers termed epoxides.
  • Soluble epoxide hydrolase (“sEH”) is an enzyme which in endothelial, smooth muscle and other cell types converts EETs to dihydroxy derivatives called
  • DHETs dihydroxyeicosatrienoic acids
  • treat refers to any method of alleviating or abrogating a disease or its attendant symptoms.
  • terapéuticaally effective amount refers to that amount of the compound being administered sufficient to prevent or decrease the development of one or more of the symptoms of the disease, condition or disorder being treated.
  • modulate refers to the ability of a compound to increase or decrease the function, or activity, of the associated activity (e.g., soluble epoxide hydrolase).
  • Modulation as used herein in its various forms, is meant to include antagonism and partial antagonism of the activity associated with sEH.
  • Inhibitors of sEH are compounds that, e.g., bind to, partially or totally block the enzyme's activity.
  • compound as used herein is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active derivatives, including, but not limited to, salts, prodrug conjugates such as esters and amides, metabolites and the like.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
  • sEH-mediated disease or condition refers to a disease or condition characterized by less than or greater than normal, sEH activity.
  • a sEH-mediated disease or condition is one in which modulation of sEH results in some effect on the underlying condition or disease (e.g., a sEH inhibitor or antagonist results in some improvement in patient well-being in at least some patients).
  • Plasmama refers to the tissue characteristic of an organ, as distinguished from associated connective or supporting tissues.
  • COPD Chronic Obstructive Pulmonary Disease
  • COPD is generally defined as a disorder characterized by reduced maximal expiratory flow and slow forced emptying of the lungs. COPD is considered to encompass two related conditions, emphysema and chronic bronchitis. COPD can be diagnosed by the general practitioner using art recognized techniques, such as the patient's forced vital capacity (“FVC”), the maximum volume of air that can be forceably expelled after a maximal inhalation. In the offices of general practitioners, the FVC is typically approximated by a 6 second maximal exhalation through a spirometer.
  • FVC forced vital capacity
  • Emphysema is a disease of the lungs characterized by permanent destructive enlargement of the airspaces distal to the terminal bronchioles without obvious fibrosis.
  • Chronic bronchitis is a disease of the lungs characterized by chronic bronchial secretions which last for most days of a month, for three months a year, for two years.
  • obstructive pulmonary disease and “obstructive lung disease” refer to obstructive diseases, as opposed to restrictive diseases. These diseases particularly include COPD, bronchial asthma and small airway disease.
  • Small airway disease There is a distinct minority of patients whose airflow obstruction is due, solely or predominantly to involvement of the small airways. These are defined as airways less than 2 mm in diameter and correspond to small cartilaginous bronchi, terminal bronchioles and respiratory bronchioles. Small airway disease (SAD) represents luminal obstruction by inflammatory and fibrotic changes that increase airway resistance. The obstruction may be transient or permanent.
  • interstitial lung diseases are a group of conditions involving the alveolar walls, perialveolar tissues, and contiguous supporting structures.
  • the tissue between the air sacs of the lung is the interstitium, and this is the tissue affected by fibrosis in the disease.
  • Persons with the disease have difficulty breathing in because of the stiffness of the lung tissue but, in contrast to persons with obstructive lung disease, have no difficulty breathing out.
  • the definition, diagnosis and treatment of interstitial lung diseases are well known in the art.
  • Idiopathic pulmonary fibrosis or “IPF,” is considered the prototype ILD.
  • BAL Bronchoalveolar lavage
  • alkyl refers to a saturated hydrocarbon radical which may be straight-chain or branched-chain (for example, ethyl, isopropyl, t-amyl, or 2,5- dimethylhexyl). This definition applies both when the term is used alone and when it is used as part of a compound term, such as "aralkyl,” “alkylamino,”alkylaryl”and similar terms.
  • alkyl groups are those containing 1 to 24 carbon atoms. All numerical ranges in this specification and claims are intended to be inclusive of their upper and lower limits. Lower alkyl refers to those alkyl groups having 1 to 4 carbon atoms.
  • alkyl and heteroalkyl groups may be attached to other moieties at any position on the alkyl or heteroalkyl radical which would otherwise be occupied by a hydrogen atom (such as, for example, 2-pentyl, 2-methylpent-l -yl and 2-propyloxy).
  • Divalent alkyl groups may be referred to as "alkylene", and divalent heteroalkyl groups may be referred to as “heteroalkylene” such as those groups used as linkers in the present invention.
  • the alkyl, alkylene, and heteroalkyl moieties may also be optionally substituted with halogen atoms, or other groups such as oxo, cyano, nitro, alkyl, alkylamino, carboxyl, hydroxyl, alkoxy, aryloxy, and the like.
  • cycloalkyl and cycloalkylene refer to a saturated hydrocarbon ring and includes bicyclic and polycyclic rings.
  • cycloalkyl and cycloalkylene groups having one or more heteroatom (e.g., N, O, or S) in place of a carbon ring atom may be referred to as “heterocycloalkyl” and “heterocycloalkylene,” respectively.
  • heterocycloalkyl and heteroaryl groups are, for example, cyclohexyl, norbornyl, adamantyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, and the like.
  • cycloalkyl and heterocycloalkyl moieties may also be optionally substituted with halogen atoms, or other groups such as nitro, alkyl, alkylamino, carboxyl, alkoxy, aryloxy and the like.
  • cycloalkyl and cycloalkylene moieties are those having 3 to 12 carbon atoms in the ring (e.g., cyclohexyl, cyclooctyl, norbornyl, adamantyl, and the like).
  • heterocycloalkyl and heterocycloalkylene moieties are those having 1 to 3 hetero atoms (preferably N, O and/or S) substituting for carbon in a 5 or 6-membered ring (e.g., morpholinyl, morpholinylene thiomorpholinyl, thiomorpholinylene,
  • (cycloalkyl)alkyl refers to a group having a cycloalkyl moiety attached to an alkyl moiety. Examples are cyclohexylmethyl, cyclohexylethyl, and cyclopentylpropyl.
  • alkenyl refers to an alkyl group as described above which contains one or more sites of unsaturation that is a double bond.
  • alkynyl refers to an alkyl group as described above which contains one or more sites of unsaturation that is a triple bond.
  • alkoxy refers to an alkyl radical as described above which also bears an oxygen substituent which is capable of covalent attachment to another hydrocarbon radical (such as, for example, methoxy, ethoxy, aryloxy and t-butoxy).
  • aryl refers to an aromatic carbocyclic substituent which may be a single ring or multiple rings which are fused together, linked covalently or linked to a common group such as an ethylene or methylene moiety.
  • aryl groups having a heteroatom e.g. N, O or S
  • heteroaryl e.g. N, O or S
  • Examples of aryl and heteroaryl groups are, for example, phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl- l -ethyl, thienyl, pyridyl and quinoxalyl.
  • aryl and heteroaryl moieties may also be optionally substituted with halogen atoms, or other groups such as nitro, alkyl, alkylamino, carboxyl, alkoxy, phenoxy and the like. Additionally, the aryl and heteroaryl groups may be attached to other moieties at any position on the aryl or heteroaryl radical which would otherwise be occupied by a hydrogen atom (such as, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl). Divalent aryl groups are "arylene", and divalent heteroaryl groups are referred to as "heteroarylene” such as those groups used as linkers in the present invention.
  • arylalkyl refers to an aryl radical attached directly to an alkyl group, an alkenyl group, or an oxygen which is attached to an alkyl group, respectively.
  • aryl as part of a combined term as above is meant to include heteroaryl as well.
  • halo or halogen
  • substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • C ⁇ -C haloalkyl is mean to include trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • hetero as used in a “heteroatom-containing alkyl group” (a)
  • heteroalkyl group or a “heteroatom-containing aryl group” (a “heteroaryl” group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur or more that none non-carbon atom (e.g., sulfonamide).
  • heteroalkyl refers to an alkyl substituent that is heteroatom- containing
  • heterocyclic refers to a cyclic substituent that is heteroatom- containing
  • heteroaryl and heteroaromatic respectively refer to “aryl” and “aromatic” substituents that are heteroatom-containing, and the like.
  • heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.
  • heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1 ,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, etc.
  • hydrophobic radical or “hydrophobic group” refers to a group which lowers the water solubility of a molecule.
  • hydrophobic radicals are groups containing at least 3 carbon atoms.
  • carboxylic acid analog refers to a variety of groups having an acidic moiety that are capable of mimicking a carboxylic acid residue. Examples of such groups are sulfonic acids, sulfinic acids, phosphoric acids, phosphonic acids, phosphinic acids, sulfonamides, and heterocyclic moieties such as, for example, imidazoles, triazoles and tetrazoles.
  • substituted refers to the replacement of an atom or a group of atoms of a compound with another atom or group of atoms.
  • an atom or a group of atoms may be substituted with one or more of the following substituents or groups: halo, cyano, nitro, alkyl, alkylamino, hydroxyalkyl, haloalkyl, carboxyl, hydroxyl, alkoxy,
  • arylcarbonylamino azido, nitro, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl.
  • unsubstituted refers to a native compound that lacks replacement of an atom or a group of atoms.
  • sulfonyl fluoride and “fluorosulfonyl” are used herein generically to refer to substituents comprising -S0 2 F attached via the sulfur atom thereof to a carbon, oxygen or nitrogen. Methods of preparing sulfonyl fluoride substituents are well known in the art.
  • the present invention is based on the discovery that the presence of a
  • fluorosulfonyl group on the sEH inhibitor (e.g., attached to a carbon, nitrogen, or oxygen atom thereof) provides a sEH inhibitor with improved physical properties.
  • the present invention provides soluble epoxide hydrolase inhibitors represented by the Formula (I): and their pharmaceutically acceptable salts; wherein the inhibitor comprises at least one S0 2 F group covalently bonded to a carbon, oxygen or nitrogen atom thereof, preferably on an R 1 group or a P 1 group.
  • R 1 is selected from the group consisting of alkyl, heteroalkyl, C5-C12 cycloalkyl, C5-C12 cycloalkylalkyl, C 5 -C ) 2 cycloalkylheteroalkyl, arylalkyl, arylheteroalkyl, aryl, and heteroaryl; and R 1 can be substituted or unsubstituted.
  • P 2 is a secondary pharmacophore selected from the group consisting of -NH-, -OC(0)0-, -C(O)-, -CH(OH)-, -0(CH 2 CH 2 0) q -, -C(0)0-, -OC(O)-, -NHC(NH)NH-,
  • n and m are each independently 0 or 1 , at least one of n or m is 1 , and the subscript q is 0 to 6.
  • L 1 represents a first linking group that is selected from the group consisting of a covalent bond, C i-C 6 alkylene, C3-C6 cycloalkylene, 5-membered ring heterocycloalkylene comprising 1 to 3 heteroatoms selected from N, O, and S, 6- membered ring heterocycloalkylene comprising 1 to 3 heteroatoms selected from N, O, and S, arylene, and heteroarylene; when m is 1 , L represents a second linking group selected from the group consisting of a covalent bond, Ci -C !
  • a preferred P 1 group is ureido (-NHC(O)NH-).
  • a preferred R 1 is aryl, particularly phenyl, which can include one or more substituent groups.
  • Non-limiting examples of some preferred P 3 groups include substituted or unsubstituted aryl (e.g., phenyl, optionally including one or more substituent), heterocyclyl (e.g., piperidinyl and N-substituted piperidinyl).
  • the inhibitor compound of Formula (I) can be represented by Formula (II):
  • P 1 is as defined for formula (I), but preferably is ureido (-NHC(O)NH-); each x independently is 0, 1 , 2, or 3, provided that at least on x is not 0; and each X 1
  • C 2 -C 6 alkenyl independently is selected from the group consisting of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C(, haloalkyl (e.g., CF 3 , CH 2 CF 3 , CC1 3 , etc.), aryl, heteroaryl, heterocyclyl,
  • R 3 can be substituted or unsubstituted and is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C C 6 haloalkyl (e.g., CF 3 , CH 2 CF 3 , CC1 3 , etc.), aryl, heteroaryl, heterocyclyl, and C 3 -C 8 cycloalkyl; and wherein at least one X 1 comprises an S0 2 F moiety (i.e.,
  • the inhibitor compound of Formula (I) can be represented by Formula (III): wherein P 1 is as defined for Formula (I), but preferably is ureido (-NHC(O)NH-); x is 0, 1 , 2, or 3; X 1 is defined as in Formula (II); X 2 is selected from -C(0)NF1R 3 ,
  • S0 2 F moiety i.e., a group selected from - S0 2 F, -CH 2 CH 2 S0 2
  • the inhibitor compound of Formula (I) can be represented by Formula (IV):
  • P 1 is as defined for Formula (I), but preferably is ureido (-NHC(O)NH-); P 2 is as defined for Formula (I), but preferably is -0-; x is defined as in Formula (II); and X 1 is defined as in Formula (II).
  • Treatment of diseases modulated by soluble epoxide hydrolases generally involves administering to a subject in need of such treatment an effective amount of a compound of Formula (I), e.g., a compound of Formula (II), (III), or (IV).
  • a compound of Formula (I) e.g., a compound of Formula (II), (III), or (IV).
  • the dose, frequency and timing of such administering will depend in large part on the selected therapeutic agent, the nature of the condition being treated, the condition of the subject including age, weight and presence of other conditions or disorders, the formulation being administered and the discretion of the attending physician.
  • the compositions and compounds of the invention and the pharmaceutically acceptable salts thereof are administered via oral, parenteral, subcutaneous, intramuscular, intravenous or topical routes.
  • the compounds are administered in dosages ranging from about 2 mg up to about 2,000 mg per day, although variations will necessarily occur depending, as noted above, on the disease target, the patient, and the route of administration. Dosages are administered orally in the range of about 0.05 mg/kg to about 20 mg/kg, more preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg of body weight per day.
  • the dosage employed for the topical administration will, of course, depend on the size of the area being treated.
  • the sEH inhibitor compounds can be formulated as pharmaceutical compositions for administration as described herein.
  • Such therapeutic compounds can be formulated as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, vehicle, or diluent, such as an aqueous buffer at a physiologically acceptable pH (e.g., pH 7 to 8.5), a polymer-based nanoparticle vehicle, a liposome, and the like.
  • compositions can be delivered in any suitable dosage form, such as a liquid, gel, solid, cream, or paste dosage form.
  • the compositions can be adapted to give sustained release of the compound of the sEH inhibitor compounds.
  • compositions comprising therapeutic compounds of Formula (I) can be administered to a subject or patient in a therapeutically effective amount to treat diseases or conditions described herein.
  • the pharmaceutical compositions include, but are not limited to, those forms suitable for oral, rectal, nasal, topical, (including buccal and sublingual), transdermal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration.
  • the compositions can, where appropriate, be conveniently provided in discrete dosage units.
  • the pharmaceutical compositions of the invention can be prepared by any of the methods well known in the pharmaceutical arts.
  • compositions suitable for oral administration include capsules, cachets, or tablets, each containing a predetermined amount of one or more of the compounds of Formula (I), as a powder or granules.
  • the oral composition is a solution, a suspension, or an emulsion.
  • the compounds of Formula (I) can be provided as a bolus, electuary, or paste.
  • Tablets and capsules for oral administration can contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, colorants, flavoring agents, preservatives, or wetting agents.
  • the tablets can be coated according to methods well known in the art, if desired.
  • Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs.
  • the compositions can be provided as a dry product for constitution with water or another suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, nonaqueous vehicles (which may include edible oils), preservatives, and the like.
  • the additives, excipients, and the like typically will be included in the compositions for oral administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.
  • the compounds of Formula (I) will be included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts.
  • compositions for parenteral administration can be provided in unit dose form in ampoules, pre-filled syringes, small volume infusion, or in multi-dose containers, and preferably include an added preservative.
  • the compositions for parenteral administration can be suspensions, solutions, or emulsions, and can contain excipients such as suspending agents, stabilizing agent, and dispersing agents.
  • the compounds of Formula (I) can be provided in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen- free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen- free water
  • compositions for topical administration of the compounds to the epidermis can be formulated as ointments, creams, lotions, gels, or as a transdermal patch.
  • transdermal patches can contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol, t-anethole, and the like.
  • Ointments and creams can, for example, include an aqueous or oily base with the addition of suitable thickening agents, gelling agents, colorants, and the like.
  • Lotions and creams can include an aqueous or oily base and typically also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, coloring agents, and the like.
  • Gels preferably include an aqueous carrier base and include a gelling agent such as cross-linked polyacrylic acid polymer, a derivatized polysaccharide (e.g., carboxymethyl cellulose), and the like.
  • the additives, excipients, and the like typically will be included in the compositions for topical administration to the epidermis within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.
  • the compounds of Formula (I) will be included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts.
  • compositions suitable for topical administration in the mouth include lozenges comprising the compound in a flavored base, such as sucrose, acacia, or tragacanth; pastilles comprising the peptide in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the pharmaceutical compositions for topical administration in the mouth can include penetration enhancing agents, if desired.
  • the additives, excipients, and the like typically will be included in the compositions of topical oral administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.
  • a pharmaceutical composition suitable for rectal administration comprises a compound of the present invention in combination with a solid or semisolid (e.g., cream or paste) carrier or vehicle.
  • a solid or semisolid carrier or vehicle e.g., cream or paste
  • Such rectal compositions can be provided as unit dose suppositories.
  • Suitable carriers or vehicles include cocoa butter and other materials commonly used in the art.
  • the additives, excipients, and the like typically will be included in the compositions of rectal administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.
  • the compounds of Formula (I) will be included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts.
  • compositions suitable for intra-nasal administration are also encompassed by the present invention.
  • Such intra-nasal compositions comprise a compound of Formula (I) in a vehicle and suitable administration device to deliver a liquid spray, dispersible powder, or drops.
  • Drops may be formulated with an aqueous or nonaqueous base also comprising one or more dispersing agents, solubilizing agents, or suspending agents.
  • Liquid sprays are conveniently delivered from a pressurized pack, an insufflator, a nebulizer, or other convenient means of delivering an aerosol comprising the peptide.
  • Pressurized packs comprise a suitable propellant such as
  • compositions for administration by inhalation or insufflation can be provided in the form of a dry powder composition, for example, a powder mix of the compounds of Formula (I) and a suitable powder base such as lactose or starch.
  • a powder mix of the compounds of Formula (I) and a suitable powder base such as lactose or starch.
  • Such powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin packs, or blister packs, from which the powder can be administered with the aid of an inhalator or insufflator.
  • the additives, excipients, and the like typically will be included in the compositions of intra-nasal administration within a range of
  • compositions of the present invention can include one or more other therapeutic agent, such as another sEH inhibitor, e.g., as a combination therapy.
  • another sEH inhibitor e.g., as a combination therapy.
  • inhibitors of sEH can reduce hypertension.
  • Such inhibitors can be useful in controlling the blood pressure of persons with undesirably high blood pressure, including those who suffer from diabetes.
  • Compounds of Formula (I) can be administered to a subject in need of treatment for hypertension, specifically renal, hepatic, or pulmonary hypertension; inflammation, specifically renal inflammation, vascular inflammation, and lung inflammation; adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome and arthritis.
  • Compounds of the invention can also reduce damage to the kidney, and especially damage to kidneys from diabetes, as measured by albuminuria.
  • the compounds of the invention can reduce kidney deterioration (nephropathy) from diabetes even in individuals who do not have high blood pressure.
  • the conditions of therapeutic administration are as described above.
  • cis-Epoxyeicosantrienoic acids (“EETs”) can be used in conjunction with the compounds of the invention to further reduce kidney damage.
  • EETs which are epoxides of arachidonic acid, are known to be effectors of blood pressure, regulators of inflammation, and modulators of vascular permeability. Hydrolysis of the epoxides by sEH diminishes this activity.
  • EETs are well known compounds. EETs useful in the methods of the present invention include 14,15-EET, 8,9-EET and 1 1 ,12-EET, and 5,6 EETs, in that order of preference. Preferably, the EETs are administered as the methyl ester, which is more stable. Persons of skill will recognize that the EETs are regioisomers, such as 8S,9R- and 14R,15S-EET. 8,9-EET, 1 1 ,12-EET, and 14R,15S-EET, are commercially available from, for example, Sigma-Aldrich (catalog nos. E5516, E5641 , and E5766, respectively, Sigma- Aldrich Corp., St. Louis, MO).
  • EETs produced by the endothelium have anti-hypertensive properties and the EETs 1 1 ,12-EET and 14, 15-EET may be endothelium-derived hyperpolarizing factors (EDHFs). Additionally, EETs such as 1 1 ,12-EET have profibrinolytic effects, anti-inflammatory actions and inhibit smooth muscle cell proliferation and migration. In the context of the present invention, these favorable properties are believed to protect the vasculature and organs during renal and cardiovascular disease states.
  • sEH activity can be inhibited sufficiently to increase the levels of EETs and thus augment the effects of administering sEH inhibitors by themselves.
  • EETs to be used in conjunction with one or more sEH inhibitors to reduce nephropathy in the methods of the invention. It further permits EETs to be used in conjunction with one or more sEH inhibitors to reduce hypertension, or inflammation, or both.
  • medicaments of EETs can be made which can be administered in conjunction with one or more sEH inhibitors, or a medicament containing one or more sEH inhibitors can optionally contain one or more EETs.
  • the EETs can be administered concurrently with the sEH inhibitor, or following administration of the sEH inhibitor. It is understood that, like all drugs, inhibitors have half lives defined by the rate at which they are metabolized by or excreted from the body, and that the inhibitor will have a period following administration during which it will be present in amounts sufficient to be effective. If EETs are administered after the inhibitor is administered, therefore, it is desirable that the EETs be administered during the period during which the inhibitor will be present in amounts to be effective to delay hydrolysis of the EETs. Typically, the EET or EETs will be administered within 48 hours of
  • the EET or EETs are administered within 24 hours of the inhibitor, and even more preferably within 12 hours. In increasing order of desirability, the EET or EETs are administered within 10, 8, 6, 4, 2, hours, 1 hour, or one half hour after administration of the inhibitor. Most preferably, the EET or EETs are administered concurrently with the inhibitor.
  • the EETs, the compound of the invention, or both are provided in a material that permits them to be released over time to provide a longer duration of action.
  • Slow release coatings are well known in the pharmaceutical art; the choice of the particular slow release coating is not critical to the practice of the present invention.
  • EETs are subject to degradation under acidic conditions. Thus, if the EETs are to be administered orally, it is desirable that they are protected from degradation in the stomach.
  • EETs for oral administration may be coated to permit them to passage the acidic environment of the stomach into the basic environment of the intestines. Such coatings are well known in the art. For example, aspirin coated with so-called
  • enteric coatings is widely available commercially. Such enteric coatings may be used to protect EETs during passage through the stomach.
  • An exemplary coating is set forth in the Examples.
  • the present compounds can be used with regard to any and all forms of diabetes to the extent that they are associated with progressive damage to the kidney or kidney function.
  • the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
  • the long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints.
  • sEH inhibitors are at high risk of progression to Type 2 diabetes, and therefore at higher risk than average for diabetic nephropathy. It is therefore desirable to monitor such individuals for microalbuminuria, and to administer a sEH inhibitor and, optionally, one or more EETs, as an intervention to reduce the development of nephropathy. The practitioner may wait until microalbuminuria is seen before beginning the intervention.
  • a person can be diagnosed with metabolic syndrome without having a blood pressure of 130/85 or higher. Both persons with blood pressure of 1 30/85 or higher and persons with blood pressure below 1 30/85 can benefit from the administration of sEH inhibitors and, optionally, of one or more EETs, to slow the progression of damage to their kidneys. In some embodiments, the person has metabolic syndrome and blood pressure below 130/85.
  • Dyslipidemia or disorders of lipid metabolism is another risk factor for heart disease.
  • Such disorders include an increased level of LDL cholesterol, a reduced level of HDL cholesterol, and an increased level of triglycerides.
  • An increased level of serum cholesterol, and especially of LDL cholesterol, is associated with an increased risk of heart disease.
  • the kidneys are also damaged by such high levels. It is believed that high levels of triglycerides are associated with kidney damage.
  • levels of cholesterol over 200 mg/dL, and especially levels over 225 mg/dL would suggest that sEH inhibitors and, optionally, EETs, should be administered.
  • triglyceride levels of more than 215 mg/dL, and especially of 250 mg/dL or higher, would indicate that administration of sEH inhibitors and, optionally, of EETs, would be desirable.
  • the administration of compounds of the present invention with or without the EETs can reduce the need to administer statin drugs (HMG-CoA reductase inhibitors) to the patients, or reduce the amount of the statins needed.
  • candidates for the methods, uses and compositions of the invention have triglyceride levels over 215 mg/dL and blood pressure below 130/85. In some embodiments, the candidates have triglyceride levels over 250 mg/dL and blood pressure below 1 30/85. In some embodiments, candidates for the methods, uses and compositions of the invention have cholesterol levels over 200 mg/dL and blood pressure below 130/85. In some embodiments, the candidates have cholesterol levels over 225 mg/dL and blood pressure below 1 30/85.
  • compounds of Formula (I) inhibit proliferation of vascular smooth muscle (VSM) cells without significant cell toxicity, (e.g. specific to VSM cells). Because VSM cell proliferation is an integral process in the pathophysiology of atherosclerosis, these compounds are suitable for slowing or inhibition atherosclerosis. These compounds are useful to subjects at risk for atherosclerosis, such as individuals who have had a heart attack or a test result showing decreased blood circulation to the heart. The conditions of therapeutic administration are as described above. The present compounds are particularly useful for patients who have had percutaneous intervention, such as angioplasty to reopen a narrowed artery, to reduce or to slow the narrowing of the reopened passage by restenosis.
  • the artery is a coronary artery.
  • the compounds can be placed on stents in polymeric coatings to provide a controlled localized release to reduce restenosis.
  • Polymer compositions for implantable medical devices, such as stents, and methods for embedding agents in the polymer for controlled release are known in the art and taught, for example, in U.S. Pat. Nos. 6,335,029 to Kamath et al.; 6,322,847 to Zhong et al.; 6,299,604 to Raghab et al.; 6,290,722 to Wang et al.; 6,287,285 to Michal et al.; and 5,637,1 13 to Tartaglia et al.
  • the coating releases the inhibitor over a period of time, preferably over a period of days, weeks, or months.
  • the particular polymer or other coating chosen is not a critical part of the present invention.
  • the present compounds are useful for slowing or inhibiting the stenosis or restenosis of natural and synthetic vascular grafts.
  • the synthetic vascular graft comprises a material which releases a compound of the invention over time to slow or inhibit VSM proliferation and the consequent stenosis of the graft.
  • Hemodialysis grafts are a particular embodiment.
  • the present compounds can be used to slow or to inhibit stenosis or restenosis of blood vessels of persons who have had a heart attack, or whose test results indicate that they are at risk of a heart attack.
  • compounds of the invention are administered to reduce proliferation of VSM cells in persons who do not have hypertension.
  • compounds of the invention are used to reduce proliferation of VSM cells in persons who are being treated for hypertension, but with an agent that is not an sEH inhibitor.
  • the present compounds can be used to interfere with the proliferation of cells which exhibit inappropriate cell cycle regulation.
  • the cells are cells of a cancer.
  • the proliferation of such cells can be slowed or inhibited by contacting the cells with a compound of the invention.
  • the determination of whether a particular compound of the invention can slow or inhibit the proliferation of cells of any particular type of cancer can be determined using assays routine in the art.
  • the levels of EETs can be raised by adding EETs. VSM cells contacted with both an EET and a compound of the invention exhibited slower proliferation than cells exposed to either the EET alone or to the a compound of the invention alone.
  • the slowing or inhibition of VSM cells of a compound of the invention can be enhanced by adding an EET along with a compound of the invention.
  • an EET along with a compound of the invention.
  • this can conveniently be accomplished by embedding the EET in a coating along with a compound of the invention so that both are released once the stent or graft is in position.
  • Chronic obstructive pulmonary disease encompasses two conditions, emphysema and chronic bronchitis, which relate to damage caused to the lung by air pollution, chronic exposure to chemicals, and tobacco smoke.
  • Emphysema as a disease relates to damage to the alveoli of the lung, which results in loss of the separation between alveoli and a consequent reduction in the overall surface area available for gas exchange.
  • Chronic bronchitis relates to irritation of the bronchioles, resulting in excess production of mucin, and the consequent blocking by mucin of the airways leading to the alveoli. While persons with emphysema do not necessarily have chronic bronchitis or vice versa, it is common for persons with one of the conditions to also have the other, as well as other lung disorders.
  • sEH soluble epoxide hydrolase
  • EETs can be used in conjunction with sEH inhibitors to reduce damage to the lungs by tobacco smoke or, by extension, by occupational or environmental irritants. These findings indicate that the co-administration of sEH inhibitors and of EETs can be used to inhibit or slow the development or progression of COPD, emphysema, chronic bronchitis, or other chronic obstructive lung diseases which cause irritation to the lungs.
  • the present compounds also provide new ways of reducing the severity or progression of chronic restrictive airway diseases. While obstructive airway diseases tend to result from the destruction of the lung parenchyma, and especially of the alveoli, restrictive diseases tend to arise from the deposition of excess collagen in the parenchyma. These restrictive diseases are commonly referred to as "interstitial lung diseases", or "ILDs”, and include conditions such as idiopathic pulmonary fibrosis.
  • ILDs interstitial lung diseases
  • the methods, compositions and uses of the invention are useful for reducing the severity or progression of ILDs, such as idiopathic pulmonary fibrosis. Macrophages play a significant role in stimulating interstitial cells, particularly fibroblasts, to lay down collagen. Without wishing to be bound by theory, it is believed that neutrophils are involved in activating
  • the 1LD is idiopathic pulmonary fibrosis.
  • the ILD is one associated with an occupational or environmental exposure.
  • ILDs are asbestosis, silicosis, coal worker's pneumoconiosis, and berylliosis.
  • occupational exposure to any of a number of inorganic dusts and organic dusts is believed to be associated with mucus hypersecretion and respiratory disease, including cement dust, coke oven emissions, mica, rock dusts, cotton dust, and grain dust (for a more complete list of occupational dusts associated with these conditions, see Table 254-1 of Speizer, "Environmental Lung Diseases," Harrison's Principles of Internal Medicine, infra, at pp.
  • the ILD is sarcoidosis of the lungs. ILDs can also result from radiation in medical treatment, particularly for breast cancer, and from connective tissue or collagen diseases such as rheumatoid arthritis and systemic sclerosis. It is believed that the methods, uses and compositions of the invention can be useful in each of these interstitial lung diseases.
  • the present compounds can also be used to reduce the severity or progression of asthma. Asthma typically results in mucin hypersecretion, resulting in partial airway obstruction. Additionally, irritation of the airway results in the release of mediators which result in airway obstruction. While the lymphocytes and other immunomodulatory cells recruited to the lungs in asthma may differ from those recruited as a result of COPD or an ILD, it is expected that the invention will reduce the influx of immunomodulatory cells, such as neutrophils and eosinophils, and ameliorate the extent of obstruction. Thus, it is expected that the administration of sEH inhibitors, and the administration of sEH inhibitors in combination with EETs, will be useful in reducing airway obstruction due to asthma.
  • Inhibitors of sEH and EETs administered in conjunction with inhibitors of sEH reduce brain damage from strokes.
  • inhibitors of sEH taken prior to an ischemic stroke will reduce the area of brain damage and are likely to reduce the consequent degree of impairment.
  • the reduced area of damage should also be associated with a faster recovery from the effects of the stroke.
  • Hemorrhagic stroke differs from ischemic stroke in that the damage is largely due to compression of tissue as blood builds up in the confined space within the skull after a blood vessel ruptures, whereas in ischemic stroke, the damage is largely due to loss of oxygen supply to tissues downstream of the blockage of a blood vessel by a clot.
  • Ischemic strokes are divided into thrombotic strokes, in which a clot blocks a blood vessel in the brain, and embolic strokes, in which a clot formed elsewhere in the body is carried through the blood stream and blocks a vessel there. But, in both hemorrhagic stroke and ischemic stroke, the damage is due to the death of brain cells. Based on the results observed in our studies, however, we would expect at least some reduction in brain damage in all types of stroke and in all subtypes.
  • sEH inhibitors administered to persons with any one or more of the following conditions or risk factors high blood pressure, tobacco use, diabetes, carotid artery disease, peripheral artery disease, atrial fibrillation, transient ischemic attacks (TIAs), blood disorders such as high red blood cell counts and sickle cell disease, high blood cholesterol, obesity, alcohol use of more than one drink a day for women or two drinks a day for men, use of cocaine, a family history of stroke, a previous stroke or heart attack, or being elderly, will reduce the area of brain damaged due to a stroke. With respect to being elderly, the risk of stroke increases for every 10 years. Thus, as an individual reaches 60, 70, or 80, administration of sEH inhibitors has an increasingly larger potential benefit. As noted below, the administration of EETs in combination with one or more sEH inhibitors can be beneficial in further reducing the brain damage.
  • the sEH inhibitors and, optionally, EETs can be administered to persons who use tobacco, have carotid artery disease, have peripheral artery disease, have atrial fibrillation, have had one or more transient ischemic attacks (TIAs), have a blood disorder such as a high red blood cell count or sickle cell disease, have high blood cholesterol, are obese, use alcohol in excess of one drink a day if a woman or two drinks a day if a man, use cocaine, have a family history of stroke, have had a previous stroke or heart attack and do not have high blood pressure or diabetes, or are 60, 70, or 80 years of age or more and do not have hypertension or diabetes.
  • TAAs transient ischemic attacks
  • Clot dissolving agents such as tissue plasminogen activator (tPA) reduce the extent of damage from ischemic strokes if administered in the hours shortly after a stroke.
  • tPA tissue plasminogen activator
  • tPA is approved by the FDA for use in the first three hours after a stroke.
  • sEH inhibitors optionally with EETs
  • administration of sEH inhibitors can also reduce brain damage if administered within 6 hours after a stroke has occurred, more preferably within 5, 4, 3, or 2 hours after a stroke has occurred, with each successive shorter interval being more preferable.
  • the inhibitor or inhibitors are administered 2 hours or less or even 1 hour or less after the stroke, to maximize the reduction in brain damage.
  • Persons of skill are well aware of how to make a diagnosis of whether or not a patient has had a stroke. Such determinations are typically made in hospital emergency rooms, following standard differential diagnosis protocols and imaging procedures.
  • the sEH inhibitors and, optionally, EETs are administered to persons who have had a stroke within the last 6 hours who: use tobacco, have carotid artery disease, have peripheral artery disease, have atrial fibrillation, have had one or more transient ischemic attacks (TIAs), have a blood disorder such as a high red blood cell count or sickle cell disease, have high blood cholesterol, are obese, use alcohol in excess of one drink a day if a woman or two drinks a day if a man, use cocaine, have a family history of stroke, have had a previous stroke or heart attack and do not have high blood pressure or diabetes, or are 60, 70, or 80 years of age or more and do not have hypertension or diabetes.
  • TAAs transient ischemic attacks
  • the compounds of the present invention can be prepared by a variety of methods as outlined generally in the schemes below.
  • Scheme 1 illustrates general methods that can be used for preparation of compounds of the invention having a secondary pharmacophore that is a ketone functional group. While the scheme is provided for the synthesis of l -(4-hydroxyphenyl)-3-(4- oxodecyl)urea, one of skill in the art will understand that a number of commercially available isocyanates could be used in place of 3-chlorophenyl isocyanate, and that shorter or longer analogs of ethyl 4-aminobutyric acid or hexylbromide could also be employed.
  • Scheme 1 illustrates general methods that can be used for preparation of compounds of the invention having a secondary pharmacophore that is a ketone functional group. While the scheme is provided for the synthesis of l -(4-hydroxyphenyl)-3-(4- oxodecyl)urea, one of skill in the art will understand that a number of commercially available isocyanates could be used in place of 3-chlor
  • Borax buffer/dichloromethane S0 2 F 2 (e.g., VIKANE brand sulfuryl fluoride), 6 hours.
  • ethyl 4-aminobutyrate hydrochloride (available from Aldrich Chemical Co., Milwaukee, WI, USA) is combined with benzophenone imine at room temperature to provide intermediate (i).
  • DIBAL diisobutylaluminum hydride
  • a Grignard reagent prepared in situ
  • Oxidation of the alcohol moiety to a ketone provides (iii) which can then be deprotected to form the amino-ketone (iv).
  • Reaction of (iv) with a benzyloxy isocyanate provides the phenoxy compound (v), which is then reacted with sulfuryl fluoride (S0 2 F 2 ).
  • Reaction can be monitored by quenching the solution with methanol, then submitting the sample to LCMS.
  • the solution was concentrated by rotary evaporation, and 4-isocyanato benzenesulfonyl fluoride was obtained as a yellow oil (mixed with Et ⁇ N/HCl salt).
  • the isocyanate product can be used as it is, or dissolved in DCM then directly use for next steps.
  • This intermediate is not stable at room temperature as a crude product.
  • a rapid wash with 1M HC1, followed by saturated sodium chloride, and drying over sodium sulfate afforded a material that could be stored for up to one week;.
  • 4-isocyanatobenzenesulfonyl fluoride was obtained as yellow solid.
  • ICs determination for human sEH Inhibitors ICso values for the sEH inhibitors were determined by fluorescent according to published procedures. IC 5 o, the concentration of the inhibitor that blocks 50% of the enzyme activity, was determined based on regression of at least five datum points with a minimum of two points in the linear region of the curve on either side of the ICso.
  • FRET-Displacement assay procedure The Forster Resonance Energy Transfer (FRET) assay was carried out as described in Lee et al., Analytical Biochemistry 434(2):259-268 (201 3).
  • FRET Forster Resonance Energy Transfer
  • the inhibitor stock solution 1 0 mM, DMSO
  • sEH was diluted to desired
  • PB sodium phosphate buffer
  • All buffer used in this assay was filtered by sterilized filtration unit (Millipore ⁇ Durapore ⁇ PVDF Membrane, pore size: 0.22 ⁇ ).
  • the enzyme-ligand complex was titrated with different sEH inhibitors at varying concentration until no more fluorescence quenching was observed. The relative fluorescence intensity was plotted against the concentration of inhibitor.
  • the sEH-ACPU mixture (20 nM, 100 mM sodium phosphate, 0.1 % gelatin, pH 7.4, 150 uL) was added to each well.
  • the baseline fluorescence (F 0 ) ( ⁇ ⁇ 0 ⁇ ; ⁇ at 280 nm, Emission at 450 nm) of the samples was measured after the z-position and gain were optimized automatically by the fluorometers. The z and gain value was noted and will be used for the later fluorescent measurement. Because DMSO has been known to quench fluorescence. 1 % DMSO in PB was served as a control (F DMSO )- The desired concentration of inhibitors which is the concentration that 100% of sEH was bound to inhibitor, was added at the first well and was further diluted by 2-fold across the rest of the wells. Based on our study, 12 data points which correspond to 12 different concentrations of the inhibitor, should have enough data to calculate the accurate K for the inhibitors.
  • the samples were incubated at 30 °C for 1.5 hours. Then, the fluorescence ( exc itation at 280 nm, em i ss ion at 450 nm) of the samples was measured using the z-position and gain values that previously obtained. The obtained fluorescence signals were transformed as below and were used to calculated the K ⁇ of the inhibitors according to "Curve fitting" section below.
  • the displacement assay is based on a three-state equilibrium binding model. This is modeled as described below (Eq 1 ):
  • [RL] stands for receptor or enzyme-reporting ligand complex.
  • the three-state equilibrium (Eq 1 ) consists of the sEH -inhibitor complex, sEH and sEH-reporting ligand complex.
  • the relative fluorescence intensity (F ? ) was plotted against the concentration of sEH inhibitor and the resulting curve was fitted into equation (Eq 2) derived by Wang et al. for three-state equilibrium.
  • Relative Fluorescence (observed fluorescence - fluorescence at saturation)/(initiated fluorescence - fluorescence at saturation)
  • R the total concentration of sEH
  • Ken The dissociation constant of reporting ligand (found by fluorescent binding assay), and ;
  • the sEH (8 ⁇ ) was pre-incubated with the selected inhibitor (8.8 ⁇ , 100 mM PB buffer, pH 7.4) for 1.5 h at rt.
  • the sEH-inhibitor complex was then diluted 40 times with ACPU (20 ⁇ , 100 mM sodium phosphate buffer, pH 7.4).
  • the fluorescence ⁇ excitation at 280 nm, e mission at 450 nm) was monitored immediately for every 30s up to 5100s.
  • the fluorescence Emission at 450 nm) data was plotted against time (s). The resulting curve was fitted to single exponential growth and the relative k 0/ j was obtained.
  • d k 0jj was determined by FRET-based displacement assay described by Lee et al.
  • a pre- incubated human sEH-inhibitor complex (8 ⁇ ) was diluted by 40 times by fluorescent reporter-APCU (2 ⁇ , 0.1 M Sodium Phosphate, pH 7.4).
  • f eLogP stands for experimental log P, determined by shake-flask method.
  • IC50 values in Table 2 were determined by a fluorescent substrate assay using cyano(2-methoxynapthalen-6-yl)methyl (3-phenyloxiran-2-yl)methyl carbonate) (5 ⁇ ) with human sEH ( 1 nM), as for the data in Table 1 .
  • compositions and methods that "consist essentially of or “consist of specified components or steps, in addition to compositions and methods that include other components or steps beyond those listed in the given claim or portion of the specification. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

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Abstract

La présente invention concerne des inhibiteurs de sEH substitués par fluorosulfonyle qui sont des composés représentés par la Formule (I) : où R1 est choisi dans le groupe comprenant alkyle, hétéroalkyle, cycloalkyle en C5-C12, cycloalkylalkyle en C5-C12, cycloalkylhétéroalkyle en C5-C12, arylalkyle, arylhétéroalkyle, aryle, et hétéroaryle; et R1 peut être substitué ou non substitué; P1 est un pharmacophore primaire; P2 est un pharmacophore secondaire; P3 est un pharmacophore tertiaire; et L1 et L2 sont des groupes de liaison. L'indice m vaut 0 ou 1; n vaut 0 ou 1; et le composé de Formule (I) comprend au moins un groupe S02F ("fluorosulfonyle") lié par covalence à ce dernier.
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CN114213286A (zh) * 2021-12-13 2022-03-22 湖北文理学院 一种脲类衍生物的合成方法
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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US20080227780A1 (en) * 2007-03-13 2008-09-18 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
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US20090247521A1 (en) * 2007-12-28 2009-10-01 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114213286A (zh) * 2021-12-13 2022-03-22 湖北文理学院 一种脲类衍生物的合成方法
CN114213286B (zh) * 2021-12-13 2022-12-30 湖北文理学院 一种脲类衍生物的合成方法
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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