US20190111025A1 - Mofezolac derivatives as multi-functions selective cox-1 inhibitors - Google Patents

Mofezolac derivatives as multi-functions selective cox-1 inhibitors Download PDF

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US20190111025A1
US20190111025A1 US16/097,126 US201716097126A US2019111025A1 US 20190111025 A1 US20190111025 A1 US 20190111025A1 US 201716097126 A US201716097126 A US 201716097126A US 2019111025 A1 US2019111025 A1 US 2019111025A1
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cox
mofezolac
lps
aromatic protons
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Antonio Scilimati
Maria Grazia Perrone
Paola Vitale
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Universita degli Studi di Bari Aldo Moro
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • the invention relates to a new class of compounds targeting COX-1.
  • the invention also relates to the use of some of such compounds as a tool to investigate the structure and function of the enzyme, in the treatment targeting COX-1 or detection of COX-1 in relating disorders or diseases such as cancer and neuroinflammation (i.e. the inflammation of the nervous tissue), in particular in neurological (e.g. autism spectrum disorders) and neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases), and in gynecological tumour (e.g. ovarian cancer), neck and head tumor, and haematological tumours (e.g. multiple myeloma) and in the detection of COX-1 in “in vitro” (cells and tissues) and in “in vivo”.
  • disorders or diseases i.e. the inflammation of the nervous tissue
  • neurological e.g. autism spectrum disorders
  • COXs Cyclooxygenases
  • COX-1 plays a previously unrecognized role in the neuroinflammation. Genetic ablation or pharmacological inhibition of COX-1 catalytic activity attenuates the inflammatory response and neuronal loss.
  • the treatment of LPS-stimulated microglial cell (a worldwide accepted neuroinflammation model) by selective COX-1 inhibitors (P6, P10, SC-560, aspirin) and coxibs (celecoxib and etoricoxib) determines the total suppression of the expression of either COX-1 or COX-2 by their respective selective inhibitors; NF-kB remained almost completely inactive in the presence of coxibs, as expected, and totally inactive in the presence of P6; P6 also markedly counteracted LPS enhancing cPGES mRNA expression and PGE 2 production.
  • COX-1 is predominantly localized in microglia, its highly selective inhibition, rather than COX-2 (by coxibs), is more likely to reduce neuroinflammation and hence should be considered as a potential therapeutic approach to treat neuroinflammation and pharmacologically prevent neurological (e.g. autism spectrum disorders) and neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases) with a marked inflammatory component [Scilimati et al. Pharmacol. Res. 65 (2012) 137-148].
  • tNSAIDs non-steroidal anti-inflammatory drugs
  • COX-1 protein is moderately to highly express in 99% of high-grade tumours and COX-1 expression is significantly higher than COX-2 in high-grade tumours, and across all serous tumours compared to endometrioid, mucinous, and clear cell tumours.
  • COX-1 as an ovarian cancer biomarker.
  • Another noteworthy use of some of the new compounds is that being constituted by two COX-inhibitory moieties bond by a linker of different length or constituted by an COX-inhibitory portion and the COX-substrate are tools to investigated COX structure and function.
  • the inhibitory portion is mofezolac, a known highly selective COX-1 inhibitor, and the arachidonic acid is the substrate part of these compounds.
  • Such an investigation is needed because the chemical features of a compound that make it a selective COX-1 inhibitor are not yet definitively identified. Almost fifty amino acids of the COX catalytic site are involved in the inhibitor/substrate recognition.
  • Known structure-activity relationship (SAR)investigations do not provide yet indications to project a highly selective COX-1 inhibitor.
  • the present invention relates to new compounds endowed with high affinity and selectivity for COX-1 as well as good pharmacokinetic properties.
  • the present invention relates also to new compounds targeting the COX-1 and able to cross the blood-brain barrier and hence useful to treat the neuroinflammation.
  • the present invention relates also to compounds capable to detect the COX presence in cells and tissues (healthy, representative of diseases, inflammed and tumours) and compounds to be used as tools to study the COX structure and function.
  • object of the present invention is a family of compounds having the general formula as indicated in claim 1 .
  • neurological e.g. autism spectrum disorders
  • neurodegenerative diseases e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases.
  • a third object of the invention are compounds selected from the above-indicated families for use as medicaments, advantageously for use in the treatment of any condition susceptible of being improved or prevented by selective inhibition of COX-1.
  • COX-1 relating disorders such as cancer more in particular in gynecological tumour (e.g. ovarian cancer), neck and head tumor, and haematological tumours (e.g. multiple myeloma), and in the treatment of inflammation in neurological (e.g. autism spectrum disorders) or neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases).
  • gynecological tumour e.g. ovarian cancer
  • neck and head tumor e.g. multiple myeloma
  • haematological tumours e.g. multiple myeloma
  • inflammation in neurological e.g. autism spectrum disorders
  • neurodegenerative diseases
  • a fourth object of the invention is the use of compounds selected from the above-indicated families for detecting and treating neuroinflammation targeting COX-1 and, hence, neurological and neurodegenerative diseases, because such selected compounds are able to cross the blood-brain barrier (through GLUT carriers) and then reach the central nervous system.
  • a fifth object of the invention is the use of compounds selected from the above-indicated families for detecting in vitro, ex-vivo or in vivo the presence of COX-1 in cells and tissues.
  • a sixth object of the invention is the use of compounds selected from the above-indicated families to investigate COX-1 structure and function.
  • a seventh object of the invention are the compounds herein disclosed isotopically radiolabeled.
  • a further object of the invention is a pharmaceutical composition comprising the compounds of the invention and a pharmacologically acceptable excipient.
  • FIG. 2 Schematic representation of Caco-2 monolayer in a transwell system.
  • FIG. 3 Perkin-Elmer Operetta images (20 ⁇ magnification) acquired from Hoechst 33342 (a,a′) and Alexa Fluor® 594 (b, b′) channels (a,b: anti-Glut-1 mouse monoclonal antibody; a′,b′: non immune control). Merged images of a-b ad a′-b′ are shown in c and c′, respectively.
  • FIG. 4 Calibration plot of GALMOF 0 .
  • FIG. 5 HPLC elution profile of GALMOF 0 .
  • FIG. 8 HPLC elution profile of GALMOF 0 incubated with the microsomes and the NADPH regeneration system.
  • GALMOF 0 was found to be metabolically stable. In fact, 96% residual GALMOF 0 was found after 30 min of treatment with microsomes.
  • FIG. 9 HPLC elution profile of GALMOF 0 incubated with only the microsomes.
  • C micr 70.51 mAU*s is the concentration after the incubation.
  • FIG. 2S GFAP immunoreactivity in the hippocampus (A), caudate—putamen (B), frontal lobe (C) and substantia nigra (D), in slices of control (CTR), vehicle of LPS (v-LPS), LPS, mofezolac and LPS (M-LPS) treated mice.
  • A hippocampus
  • B caudate—putamen
  • C frontal lobe
  • D substantia nigra
  • CTR slices of control
  • v-LPS vehicle of LPS
  • LPS mofezolac and LPS
  • FIG. 3S Iba-1 immunoreactivity in the hippocampus (A), caudate—putamen (B), frontal lobe (C) and substantia nigra (D), in slices of control (CTR), vehicle of LPS (v-LPS), LPS, mofezolac and LPS (M-LPS) treated mice.
  • FIG. 4S Effect of mofezolac on GFAP, Iba-1, COXs and pIkB ⁇ expression in caudate-putamen from mice treated with LPS alone and LPS in the presence of mofezolac.
  • the quantification of relative band intensities was expressed as relative density, after normalization against ⁇ -actin densitometry. Values represents the means ⁇ SE of three independent experiments.
  • FIG. 5S Effect of mofezolac on GFAP, Iba-1, COXs and pIkB ⁇ expression in hippocampus from mice treated with LPS alone and LPS in the presence of mofezolac.
  • the quantification of relative band intensities was expressed as relative density, after normalization against ⁇ -actin densitometry. Values represents the means ⁇ SE of three independent experiments.
  • FIG. 6S Effect of mofezolac on GFAP, Iba-1, COXs and pIkB ⁇ expression in frontal lobe from mice treated with LPS alone and LPS in the presence of mofezolac.
  • FIG. 8S Effects of COX-1 inhibitors on the COXs expression and NF-kB phosphorylation induced by LPS in BV2 microglial cells. Total protein was subjected to SDS-PAGE, followed by immunoblotting using pIkB ⁇ antibody. The quantification of relative band intensities was expressed as relative density, after normalization against ⁇ -actin densitometry. Each bar represents the means ⁇ SE of three independent experiments. BV2 microglial cells incubated with medium alone (control) or treated with LPS alone or in presence of the P6 and mofezolac (M) for 48 h. ⁇ ⁇ ⁇ p ⁇ 0.001 vs control, *** p ⁇ 0.001 vs LPS alone.
  • M mofezolac
  • the invention relates to a family of novel compounds having the following general formula I thereof:
  • R-G is OH or OCH 3 ;
  • R is a linker selected from benzidine, phenylenediamine, ⁇ , ⁇ ′-diamino-p-xylene, alkyldiamine, O—(CH 2 ) n or NH—(CH 2 ) n , NH—(CH 2 ) n CO or NH—(CH 2 ) n NH
  • n is from 0 to 12 and
  • G is selected from the group consisting of a sugar, an amino acid, a fluorescent moiety, mofezolac or arachidonic acid, hydrogen, OH, OCH 3 ,
  • the compound having the following formula I wherein G is selected from: galactose, glucose, fructose, glycine, valine, isoleucine, alanine, arginine, leucine, asparagine, lysine, histidine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, proline, selenocysteine, serine, tyrosine, mofezolac or arachidonic acid, nile blue or 6-(7-nitrobenzenfurazan-4-ylamino)hexanoic acid (NBD-C 6 acid) or 6-(7-nitrobenzenfurazan-4-ylamino)dodecanoic acid (NBD-C 12 acid) or rhodamine.
  • G is selected from: galactose, glucose, fructose, glycine, valine, isoleucine, a
  • the compound having the formula (I) reported above wherein R-G is OH or OCH 3 that correspond to mofezolac or its methyl ester for use in the treatment of neuroinflammation, in particular for use in the treatment of neurological (e.g. autism spectrum disorders) and/or neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases).
  • neurological e.g. autism spectrum disorders
  • neurodegenerative diseases e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases.
  • the mofezolac moiety [3,4-bis(4-methoxyphenyl)isoxazole] in the compounds with formula (I) can be replaced by P6-COOH 2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetic acid, a derivative of P6 [5-chlorofuran-2-yl)-3-phenylisoxazole] and, R is HN(CH 2 ) 4 NH and G is rhodamine.
  • the compounds of the present invention are useful in the treatment of inflammatory processes that are tightly connected to the brain degenerative processes.
  • Neuroinflammation is the primary step in the progression of several neurodegenerative disorders such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, and HIV encephalitis, and in mental diseases such as the autism spectrum disorders.
  • Cyclooxygenase(COX)-1 exerts an important role in the neuroinflammatory process being constitutively expressed in microglia which in turn is activated by central nervous system (CNS) injuries.
  • CNS central nervous system
  • Microglial COX-1 rapidly responses to these inciting stimuli by producing the pro-inflammatory prostaglandin, such as the PGE 2 .
  • a selective COX-1 inhibition is expected to be useful in treating early stage of neuroinflammation.
  • the blood-brain barrier (BBB) crossing by drugs is one of the challenge of all scientists which target central nervous system diseases.
  • the low permeability of BBB is the major impediment for drugs targeting CNS.
  • Some of the compounds of the present invention are capable to “carry” the entire molecule into the CNS by the GLUT-1 carrier, which is located on the membrane of vascular endothelial cells.
  • mofezolac conjugated with D-galactose by linkers with different length may be used in pharmaceutical composition for the treatment of inflammatory processes and the treatment of several diseases selected for example from the group consisting of cancer, neuroinflammation, neurological diseases, neurodegenerative diseases, ovarian cancer, neck cancer and head cancer.
  • diseases selected for example from the group consisting of cancer, neuroinflammation, neurological diseases, neurodegenerative diseases, ovarian cancer, neck cancer and head cancer.
  • neurodegenerative disorders are Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, and HIV encephalitis.
  • the preferred compounds are GALMOF 0 , GALMOF 5 and GALMOF 11 .
  • G is a fluorescent probe, in particular when G is Nile blue or NBD-C 6 or NBD-C 12 or rhodamine, are useful for in vitro, ex-vivo and in vivo diagnosis or imaging.
  • an in vivo method for diagnosis of cancer, in particular ovarian cancer comprising a step of administering to a mammal, preferably a human, an effective amount of a compound of the families described above, in particular a compound wherein G is Nile blue or NBD-C 6 or NBD-C 12 or rhodamine.
  • the Nile blue, NBDs and rhodamine probes have advantages of optical properties with NIR absorption (630 nm) and emission (670 nm) and can detect cancer cells by the fluorescence imaging method.
  • the cancer cells detect by the in vivo or in vitro or ex-vivo imaging method are ovarian cancer cells.
  • the imaging technique may be for example a fluorescence imaging method to detect COX in cancer cells/tumour tissues during surgical resection and inflamed cells and tissues. Failure to adequately recognize tumour margins and an incomplete resection may increase tumour recurrence and decrease the survival rate.
  • the effective amount administered of the compounds of the present invention will depend on the particular condition to be diagnosed, the age, weight and the overall physical condition of the particular patient as it is well known to the experts in the field.
  • the diagnostically effective amount of the compounds of the present invention to be administered before conducting the in vivo diagnosis is within a range from 0.1 ng to 100 mg per kg body weight, preferably within a range of from 1 ng to 10 mg per kg body weight.
  • It is a further object of the invention an in vitro method for diagnosis of cancer, in particular ovarian cancer comprising a step of administering an effective amount of a compound of the families described above, in particular a compound wherein G is a fluorescent probe, more in particular wherein G is Nile blue or NBDs or rhodamine, with a sample of cells or tissues.
  • the present invention also encompasses isotopically radiolabeled compounds which are identical to the compounds according to any embodiment herein disclosed but for the fact that one or more atoms are replaced by an atom having atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Example of isotopes that can be incorporated into the intermediates or compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 3 H, 11 C, 14 C, 13 N, 15 O, 18 F, respectively.
  • the incorporation of radioactive atom into the compounds of the present invention may be performed using techniques known in the art, for example by the incorporation of radioactive 11-Carbon or 18-Fluorine atom into the compounds of the present invention.
  • a further object of the invention is a diagnostic imaging composition
  • a diagnostic imaging composition comprising as imaging agents the compounds selected from the above-indicated families, in one embodiment isotopically labeled and a carrier.
  • the compounds according to Formula (I) may be administered in a single unit injectable dose.
  • Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or diluent(s).
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with the liquid carrier.
  • imaging of the organ in vivo can take place in a matter of a few minutes. However, imaging takes place, if desired, in hours or even longer, after injecting into patients. In most instances, a sufficient amount of the administered dose will accumulate in the area to be imaged within about 1 hour to permit the taking of diagnostic images.
  • Any conventional method of imaging for diagnostic purposes can be utilized in accordance with this invention as positron emission tomography (PET) or Single photon emission computed tomography (SPECT).
  • the diagnostic imaging compositions of the invention are useful for use in vivo diagnosis or imaging of a condition in which the COX-1 is the molecular target.
  • a further object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds selected from the above-indicated families and/or their “pharmacologically accepted salts”, and a pharmacologically acceptable excipient and/or carrier.
  • This pharmaceutical compositions and formulation types may contain from 0.1 to about 500 mg of the active ingredient selected from the compounds described in the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg of the active ingredient.
  • compositions of the invention are useful in the treatment or detection of COX-1 relating disorders or diseases such as cancer and neuroinflammation, in particular in neurological and neurodegenerative diseases, and in ovarian cancer, neck and head tumour.
  • a further object of the present invention is a compound selected from the above-indicated for use as medicament.
  • the compounds of the invention find therapeutic applications in the treatment of any condition susceptible of being improved or prevented by selective inhibition of COX-1, in particular in the treatment of COX-1 relating disorders such as cancer and neuroinflammation, more in particular in neurological and neurodegenerative diseases, and in ovarian cancer, neck and head tumour.
  • the compounds of formula (I) wherein G is a sugar, in particular a galactose are enable to be recognized by the sugar transporters (GLUT 1 and GLUT 2) expressed at the blood-brain barrier as also showed in the experimental section of the present application.
  • any disorders or diseases susceptible of being improved or prevented by selective inhibition of COX-1 comprising administering to a mammal requiring such treatment an effective amount of any compounds herein disclosed.
  • said disease is selected from the group consisting of cancer, neuroinflammation, neurological diseases, neurodegenerative diseases, ovarian cancer, neck cancer and head cancer, in particular in neurological (e.g. autism spectrum disorders) and/or neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases.
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • TBI traumatic brain injury
  • the effective amount administered and frequency of administration of the compounds of the present invention will depend on the particular condition to be treated, the severity of the condition to be treated, age, weight and the overall physical condition of the particular patient, as well as on other medicaments the patient is taking, as it is well known to the experts in the field.
  • the effective amount of the compounds of the invention to be administered daily or per dosage is within a range of from 0.1 ng to 100 mg per kg body weight, preferably within a range of from 1 ng to 10 mg per kg body weight.
  • Diisopropyl ethylamine (DIEA, 0.215 mL, 1.237 mmol) and methyl 5-aminopentanoate hydrochloride (100 mg, 0.60 mmol) were solubilized in dry CH 2 Cl 2 (5 mL) and stirred at 0° C. for 1 h.
  • reaction mixture was stirred at room temperature for 24 h, the organic layer was washed with water and brine, dried over Na 2 SO 4 , filtered, and the solvent removed under reduced pressure.
  • the product was isolated as a white solid (71.3 mg, 54% yield) by column chromatography (silica gel; CHCl 3 /MeOH 95:5) of the reaction crude.
  • TLC Trifluoroacetic acid
  • TMPD oxidized N,N,N′,N′-tetramethyl-p-phenylenediamine
  • Detrimental is the insertion of a C 4 -linker (GALMOF 5 ) between the two moieties (mofezolac and D-galactose) because COX-1 IC 50 is >50 ⁇ M and percentage of inhibition at 50 ⁇ M resulted to be 38 and 24% for COX-1 and COX-2, respectively.
  • GALMOF 5 C 4 -linker
  • Galmof 11 A longer spacer as for C 10 -linker (GALMOF 11 ) determines a recovery of COX-1 activity and selectivity, Galmof 11 resulted to be a potent COX-1 inhibitor with an IC 50 of 0.4 ⁇ M and a percentage of inhibition of COX-1 equal to 90% and but not selective in fact the IC 50 on COX-2 was 0.27 ⁇ M and a percentage of inhibition of 64%.
  • COX inhibitory activity a of mofezolac and GALMOF n .
  • COX-1 COX-2 Inhibitor IC 50 ⁇ M inhibition (%) b IC 50 ⁇ M inhibition (%) b mofezolac 0.0079 100 — 38 GALMOF 0 0.1 100 3.1 87 GALMOF 5 >50 38 >50 24 GALMOF 11 0.4 90 0.27 64 a Values are the means of at least three independent measurements.
  • the Papp(B ⁇ A) flux of each compound alone or in the presence of phloretin, a GLUT-1 inhibitor, has been determined. Since GLUT-1 is express in the basolateral compartment a high B ⁇ A flux means that the transport is GLUT-1 mediated because B ⁇ A flux represents the active transport.
  • a ⁇ B flux which represents the passive transport, has also been determined for each compound (Table 2).
  • GALMOF 5 the percentage of the apparent permeability reduction is of 37%, similar to that of GALMOF 0 (Papp(B ⁇ A) varies from 749 to 472 nm/sec in the presence of the GLUT-1 inhibitor.
  • GALMOF 0 metabolic stability was determined through its incubation with rat liver microsomes and monitoring the disappearance of its chromatogram peak within 30 min.
  • the in vitro test was carried out in the presence of rat liver S9 fraction (Tebu-bio, Milan, Italy).
  • the experiment started with the addition of rat microsomes (1 mg/ml) that were incubated for 30 min at 37° C. The reaction was blocked by adding an equal volume of cold CH 3 CN. The samples were centrifuged at 4,600 rpm for 15 min at 4° C. The supernatant was separated and the organic phase analysed by HPLC in the same conditions used for the samples of the “chemical stability study”.
  • C micr+NADPH is the GALMOF 0 concentration after the incubation with the microsomes and the NADPH regeneration system ( FIG. 8 ); C micr is the GALMOF 0 concentration after the incubation with only the microsomes ( FIG. 9 ).
  • NBD-C 6 6-(7-nitrobenzenfurazan-4-ylamino)hexanoic acid (NBD-C 6 , 100 mg, 0.34 mmol) [or NBD-C 12 ,12-(7-nitrobenzenfurazan-4-ylamino)dodecanoic acid] solubilized in anhydrous CH 2 Cl 2 (30 mL) under argon atmosphere, N,N-diisopropylethylamine (DIEA) (0.066 mL, 0.38 mmol). The obtained limpid orange mixture was stirred at 0° C.
  • DIEA N,N-diisopropylethylamine
  • reaction mixture was stirred at room temperature for 46 h.
  • N-(4-aminobutyl)-9-dimethylimino-9H-benzo[a]phenoxazin-5-amonium chloride 56 mg, 0.155 mmol
  • mofezolac 53 mg, 0.155 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC
  • HOBt.H 2 O 35 mg, 0.20 mmol
  • DMAP 4-dimethylaminopyridine
  • Mofezolac (3 mmol) was solubilized in anhydrous CH 2 Cl 2 contained in an argon-flushed three-necked round bottom flask, equipped with a magnetic stirrer and an argon inlet. The resulting mixture, kept under argon atmosphere, was cold to 0° C. by an ice-bath. Then, 1-hydroxybenzotriazole monohydrate (HOBt, 3 mmol)) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC, 3 mmol) were added. The yellow and limpid reaction mixture was stirred for 2 h at 0° C.
  • HOBt 1-hydroxybenzotriazole monohydrate
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • 1,4-diaminobutane (5 g, 56.72 mmol) was solubilized in anhydrous dioxane (40 mL). A yellow and limpid solution was obtained. Then, a solution of di-ter-butyl-carbonate (2.48 g, 11.34 mmol) in anhydrous dioxane (40 ml) was very slowly added by a dropping funnel. The obtained turbid reaction mixture was stirred for 16 h (overnight) at room temperature.
  • mofezolac 500 mg, 1.47 mmol was solubilized in dry DMF (35 mL). Then, N-BOC-butandiamine (800 mg, 4.25 mmol), 1-hydroxybenzotriazole monohydrate (HOBt H 2 O, 309 mg, 1.80 mmol), N,N-diisopropylethylamine (0.74 ml, 4.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC HCl, 294 mg, 1.54 mmol).
  • N-BOC-butandiamine 800 mg, 4.25 mmol
  • 1-hydroxybenzotriazole monohydrate HOBt H 2 O, 309 mg, 1.80 mmol
  • N,N-diisopropylethylamine (0.74 ml, 4.25 mmol
  • N-(4-Aminobutyl)-2-(3,4-bis(4-methoxyphenyl) isoxazol-5-yl) acetamide hydrochloride was solubilized in a mixture of EtOAc (3 mL) and 2N Na 2 CO 3 The suspension was stirred for 15 minutes at room temperature. Then, the two phases were separated and the organic portion was treated with 2N di Na 2 CO 3 (3 ⁇ 30 ml). The combined organic phases were, then treated with anhydrous Na 2 SO 4 , filtered and the solvent distilled under reduced pressure. A yellow oil was obtained.
  • HOBt H 2 O 1-hydrossibenzotriazole monohydrate
  • EDC HCl 1-(3-dimetilamminopropil)-3-etilcarbodimmide
  • arachidonic acid (0.012 ml, 0.038 mmol) was solubilized in anhydrous CH 2 Cl 2 (2 ml). Then, 1-hydrossibenzotriazole monohydrate (HOBt H 2 O, 20 mg, 0,147 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC HCl, 28 mg, 0.147 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h.
  • HOBt H 2 O 1-hydrossibenzotriazole monohydrate
  • EDC HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • N-(4-aminophenyl)-2-(3,4-bis(4-methoxyphenyl)isxsazol-5-yl)acetamide (16 mg, 0.147) and N,N-diisopropylethylamine (0,025 ml, 0,147 mmol) were solubilized in anhydrous CH 2 Cl 2 (2 ml) under argon atmosphere and stirred for 30 minutes at room temperature and then very slowly added through a dropping funnel to the first flask. The whole reaction mixture was stirred at room temperature for 16 h (overnight). Then, the reaction mixture was treated with sat. aq. NaHCO 3 (3 ⁇ 30 ml).
  • mofezolac 50 ml, 0.143 mmol was solubilized in anhydrous CH 2 Cl 2 (4 ml). Then, 1-hydrossibenzotriazole monohydrate (HOBt H 2 O, 20 mg, 0,147 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC HCl, 28 mg, 0.147 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h.
  • HOBt H 2 O 1-hydrossibenzotriazole monohydrate
  • EDC HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • arachidonic acid (0.011 ml, 0.033 mmol) was solubilized in anhydrous CH 2 Cl 2 (2 ml). Then, 1-hydrossibenzotriazole monohydrate (HOBt H 2 O, 6 mg, 0.039 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC HCl, 8 mg, 0.039 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h.
  • HOBt H 2 O 1-hydrossibenzotriazole monohydrate
  • EDC HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • N-(4′-amino-[1,1′-biphenyl]-4-yl)-2-(3,4-bis(4-mehoxyphenyl)isoxazol-5-yl)acetamide (20 mg, 0.039) and N,N-diisopropylethylamine (0,007 ml, 0,039 mmol) were solubilized in anhydrous CH 2 Cl 2 (2 ml) under argon atmosphere and stirred for 30 minutes at room temperature and then very slowly added through a dropping funnel to the first flask. The whole reaction mixture was stirred at room temperature for 16 h (overnight). Then, the reaction mixture was treated with sat. aq.
  • the target compounds were evaluated for their ability to inhibit ovine COX-1 and COX-2 enzyme catalytic activity (percent inhibition at 50 mm, unless otherwise indicated). IC 50 values were determined only for compounds that showed a reasonable COX-1 inhibitory activity (>50%) at 50 mm. Each reported IC 50 value and the percentage of inhibition (measured at 50 mm as the tested compound concentration) is the average of the results of three separate assays (triplicate). Enzyme inhibition was determined using a colorimetric COX (ovine) inhibitor screening assay kit (Cayman Chemicals, Ann Arbor, Mich., USA) following the manufacturer's instructions. Stock solutions of test compounds were dissolved in a minimum volume of DMSO.
  • MPA 290 0.95 [100] 3.5 [51] MPA326 50 [43] 0.1 [49] MPA 548 39 [54] not active MPA 551 not active not active Mof-C4-Nile blue nd nd MPA 306 — — MPA15 (DQ3) 6.0 [69] — [0] MPA361 0.013 [75] 0.12 [45] MPA448 9 [50] >50 [22] MPA434 7.1 [40] >50 MPA354 5.5 [74] >50 MPA415 0.15 [85] >50 MPA 462 0.08 [73] >50 MPA 422 >50 >50 MPA439 0.049 [66] >50 [40] MPA450 17 [50] 0.09 [60] MPA 362 16 [57] 0.8 [61] nd not determined
  • P6 (3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole) was synthesized according to Di Nunno L. et al. (2004), whereas mofezolac was synthesized following Micetich's protocol (Micetich, 1981). All the other reagents and solvents were purchased from Sigma-Aldrich (Milan, Italy) and used without any further purification.
  • LPS Lipopolysaccharide
  • Escherichia coli serotype 0127:B8 was purchased from Sigma-Aldrich (Milan, Italy).
  • the goat polyclonal a p-I ⁇ B(sc-7977) antibody (Ab) was purchased from Santa Cruz Biotechnology (DBA, Milan, Italy), COX-1 (Ab 695), COX-2 (Ab 15191) Abs were obtained from Abcam (Cambridge, UK).
  • Goat anti-rabbit IgG (sc-2004), goat anti-mouse IgG (sc-2005) and donkey anti-goat IgG (sc-2020) were purchased from Santa Cruz Biotechnology; mouse primary monoclonal antibody (mAb) anti-glial fibrillary acidic protein (GFAP) (Merck Millipore, Milan, Italy), mouse mAb anti-ionized calcium-binding adapter molecule-1 (Iba-1) (Merck Millipore). Elisa kit for PGE 2 evaluation was purchased from Cayman Chemical (Ann Arbor, Mich., USA).
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], 3,3′-diaminobenzidine and tribromoethanol were obtained from Sigma-Aldrich, Milan, Italy.
  • BV2 microglia cells (ICLC HTL 03001-Interlab Cell Line Collection) were grown in high glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal bovine serum, 100 units/ml penicillin, and 100 ⁇ g/mL streptomycin. They were maintained at 37° C. in a humidified 5% CO 2 /95% environmental air.
  • DMEM Dulbecco's modified Eagle's medium
  • microglial cells were plated, at a density of 25 ⁇ 10 4 /well in 6-well plates (Falcon) and treated with the chosen COX inhibitors (P6, mofezolac) when they reached 80% confluence.
  • COX inhibitors P6, mofezolac
  • Preliminary experiments were conducted to establish the optimal concentration and exposure times necessary for LPS (1 ⁇ g/mL) treatment, which were found to be in accordance with other reports (Bi et al., 2014; Haw et al., 2014), as well as to establish the optimal dose of the COX inhibitors and exposure times to detect their effects on LPS-stimulated BV2 microglial cell function.
  • microglial cells were 1 h pre-treated with the selective COX-1 inhibitors P6 (0.5 and 1.0 ⁇ M) or mofezolac (0.1 and 0.5 ⁇ M). Cells were then incubated for different times at 37° C. with LPS, as pro-inflammatory stimulus. Experiments included cells grown in medium alone (control).
  • MTT MTT reduction assay
  • the cells (8 ⁇ 10 3 /well) were grown in 96-well plates (Becton Dickinson Labware) in complete medium and treated with different concentration of COX inhibitors, in presence or absence of LPS. Untreated cells were used as a control.
  • a PBS 1 ⁇ solution of MTT (5 mg/mL) was prepared and added to the cell medium at a final concentration of 0.5 mg/mL.
  • Cells were incubated for 4 h at 37° C. and 5% CO 2 to allow the MTT metabolism.
  • the formazan crystals formed (from MTT) into the cells were solubilized with DMSO (Sigma-Aldrich).
  • cells were harvested and lysed by ice-cold lysis buffer [1% Triton X-100, 20 mMTris-HCl, 137 mMNaCl, 10% glycerol, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride (PMSF), 20 ⁇ M leupeptin hemisulfate salt, 0.2 U/mL aprotinin (all from Sigma-Aldrich)] for 30 min on an ice-bath.
  • ice-cold lysis buffer 1% Triton X-100, 20 mMTris-HCl, 137 mMNaCl, 10% glycerol, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride (PMSF), 20 ⁇ M leupeptin hemisulfate salt, 0.2 U/mL aprotinin (all from Sigma-Aldrich)
  • Substantia nigra pars compacta (SNpc), Hippocampus, Frontal lobe and Caudate from mice brains were minced in ice-cold PBS, washed and then homogenized in a buffer containing lysis buffer (50 mM Tris pH 8, 0.02 g/mL NaCl, 0.2% SDS, 1% Triton-X, 4 U/ml aprotinin, 2 mM leupeptin, 100 mM phenylmethanesulfonyl fluoride).
  • a buffer containing lysis buffer 50 mM Tris pH 8, 0.02 g/mL NaCl, 0.2% SDS, 1% Triton-X, 4 U/ml aprotinin, 2 mM leupeptin, 100 mM phenylmethanesulfonyl fluoride.
  • tissue and cell culture lysates were vortexed for 15-20 s and, then, centrifuged at 12,800 ⁇ g for 20 min.
  • the protein concentration in the supernatant was spectrophotometrically determined by Bradford's protein assay (Bradford, 1976).
  • mice monoclonal antibody (MoAb) anti-COX-1 and rabbit polyclonal Ab anti-COX-2 (1:1000) (both from AbCam, Cambridge, UK), rabbit polyclonal Ab anti p-IkB- ⁇ (1:200), mouse polyclonal Ab anti ⁇ -actin (1:500) (all from Santa Cruz Biotechnology), mouse MoAb anti-glial fibrillary acidic protein (GFAP) (1:200) and mouse mAb anti-ionized calcium-binding adapter molecule-1 (Iba-1) (1:200) (both from Merck Millipore) overnight at 4° C.
  • MoAb mouse monoclonal antibody
  • GFAP mouse MoAb anti-glial fibrillary acidic protein
  • Iba-1 mouse mAb anti-ionized calcium-binding adapter molecule-1
  • the membranes were washed with 0.1% Tween 20-PBS (for 20 min, 3 times) and then incubated with the secondary antibody diluted 1:2000 for 60 min. Bands were visualized by chemiluminescence detection (Invitrogen, Milan, Italy). The ⁇ -actin level was used as a protein loading control. For tissue analysis, obtained bands were normalized to the level of ⁇ -actin performed for each cerebral area tested. For cell cultures the bands were normalized to the ⁇ -actin level in each experimental condition.
  • mice Seventy adult male 129/SV mice (22-24 g body mass, 8-10 weeks of age) were purchased from Harlan-Italy and were kept under environmentally controlled conditions (20 ⁇ 2° C., 50-80% humidity, 12 h light/dark cycle, food and water ad libitum).
  • Sterotaxic injections coordinates were: 2.3 mm dorsal/ventral, 1.0 mm lateral, and 0.5 mm anterior/posterior from the bregma. Mofezolac was given 30 min prior to LPS injection (M+LPS in all the Figures).
  • mAb mouse primary monoclonal antibody
  • GFAP glial fibrillary acidic protein
  • Iba-1 mouse mAb anti-ionized calcium-binding adapter molecule-1
  • antigen-Ab complexes were visualized by sections incubation for 1 h with extravidin peroxidase (Sigma-Aldrich) diluted 1:1500 and 3,3′-diaminobenzidine oxidation in the presence of H 2 O 2 .
  • MTT assay was used to quantitatively evaluate cell viability. This was performed to verify whether the tested selective COX-1 inhibitors (P6 and mofezolac) caused toxicity in LPS-treated BV2 cell line. Preliminarily, the effect of two different concentrations of P6 (0.5 and 1 ⁇ M) and mofezolac (0.1 and 0.5 ⁇ M) on BV2 microglial cell viability was evaluated. No cell toxicity was exerted by either P6, mofezolac, LPS alone or a combination of LPS and each of the two inhibitors at 24 h. The two concentrations of P6 and mofezolac were chosen based on the basis of previous studies and their COXs IC50 values (Calvello et al., 2012).
  • Astroglial activation was characterized by immunoreactivity and immunoblotting analysis of the GFAP expression, a marker used to distinguish astrocytes from other glial cells of the CNS.
  • LPS treatment determined an increase of immunoreactive cell bodies in comparison to untreated mice suggesting astrocyte activation in different brain regions.
  • the caudate, frontal lobe, hippocampus and substantia nigra were selected in order to evaluate the astrocyte activation after different animal treatment [ FIG. 2S (A-D)].
  • Iba-1 immunoreactivity a marker of activated microglia
  • FIG. 3S LPS-treated mice Iba-1 positive cells were more numerous, showing a more intense immunoreactivity, as well as a ramified phenotype, in comparison to untreated mice [ FIG. 3S (A-D)].
  • Mofezolac administration determined the reduction of Iba-1 immunoreactivity in LPS-injected mice in all the tested brain areas [ FIG. 3S (A-D)], suggesting that mofezolac reduces, at least in part, the microglial activation induced by the neurotoxic insult.
  • COX-2 expression resultsed comparable to the level observed in cells stimulated with LPS alone ( FIG. 8S ).
  • COXs expression was also in vivo evaluated, assaying different brain regions ( FIG. 4S-7S ).
  • LPS-challenged mice exhibited increased levels of COX-1 both in comparison to controls and vehicle-LPS (vLPS) administered animals in all the different areas tested ( FIG. 4S-7S ).
  • vLPS vehicle-LPS
  • LPS challenged mice that received mofezolac treatment exhibited a significantly reduction of COX-1 expression in all brain areas tested, where reduction percentage ranged from 82 to 95% (Table 1).
  • Protein levels comparable to controls were detected in mice treated with vehicle of LPS+mofezolac, whereas in mice treated with the vehicle of mofezolac+LPS, COX-1 levels resulted comparable to those detected in LPS-treated mice ( FIGS. 4S-7S ).
  • P6 determined a reduction of 78 and 88% at 0.5 and 1 ⁇ M, respectively, whereas in the presence of mofezolac the PGE 2 production reduced of 94 and 97% at 0.5 and 1 ⁇ M, respectively.
  • mice treated with vehicle of LPS+mofezolac whereas in mice treated with vehicle of mofezolac+LPS, p-IkB ⁇ levels were comparable to those detected in LPS-treated mice ( FIGS. 4-7 ).

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