- XPO1 protein inhibitors
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The invention discloses an XPO1 (Exportin 1) inhibitor of which the structural formula F is as shown in the specification. The XPO1 inhibitor has very good solubility in water; by taking sulforaphene as a representative, the compounds have extremely high inhibitory activity to XPO1, tiny side effect, and good biosafety and bioavailability, and are very suitable for clinical application, so that the XPO1 inhibitor has a huge potential market space and economic benefits.
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Paragraph 0096-0097; 0101-0103
(2017/08/25)
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- Selective caspase inhibitors and uses thereof
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The present invention relates to compounds of Formula I, IA, II, HA, III, or IHA and their pharmaceutical uses. Particular aspects of the invention relate to the use of those compounds for the selective inhibition of one or more caspases. Also described are methods where the compounds of Formula I, IA, II, IIA, III, or IIIA are used in the prevention and/or treatment of various diseases and conditions in subjects, including caspase-mediated diseases such as sepsis, myocardial infarction, ischemic stroke, spinal cord injury (SCI), traumatic brain injury (TBI) and neurodegenerative disease (e.g. multiple sclerosis (MS) and Alzheimer's, Parkinson's, and Huntington's diseases).
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Page/Page column 100
(2017/02/28)
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- Design, synthesis, and characterization of α-ketoheterocycles that additionally target the cytosolic port Cys269 of fatty acid amide hydrolase
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A series of α-ketooxazoles incorporating electrophiles at the C5 position of the pyridyl ring of 2 (OL-135) and related compounds were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH) that additionally target the cytosolic port Cys269. From this series, a subset of the candidate inhibitors exhibited time-dependent FAAH inhibition and noncompetitive irreversible inactivation of the enzyme, consistent with the targeted Cys269 covalent alkylation or addition, and maintained or enhanced the intrinsic selectivity for FAAH versus other serine hydrolases. A preliminary in vivo assessment demonstrates that these inhibitors raise endogenous brain levels of anandamide and other FAAH substrates upon intraperitoneal (i.p.) administration to mice, with peak levels achieved within 1.5-3 h, and that the elevations of the signaling lipids were maintained >6 h, indicating that the inhibitors effectively reach and remain active in the brain, inhibiting FAAH for a sustained period.
- Otrubova, Katerina,Cravatt, Benjamin F.,Boger, Dale L.
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supporting information
p. 1079 - 1089
(2014/03/21)
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- ADENOSINE A3 RECEPTOR MODULATING COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein is a method of preventing, treating, or ameliorating one or more symptoms of an adenosine A3-mediated condition, disorder, or disease, with a compound of Formula I. Also provided herein is a method of preventing, treating, or ameliorating one or more symptoms of glaucoma or ocular hypertension. Further provided herein is a method of modulating the activity of an adenosine A3 receptor.
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- QUINAZOLINE COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are quinazoline compounds for treatment of JAK kinase mediated diseases, including JAK2 kinase-, JAK3 kinase- or TYK2 kinase-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Page/Page column 55
(2012/03/12)
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- New aldehyde and vinylsulfone proteasome inhibitors for targeted melanoma therapy
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The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [ 123I]-N-(2-diethylaminoethyl)benzamide ([123I]BZA) or [125I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([ 125I]BZ18). Influence on the cytotoxicity of the benzamide alkyl side chain length and the composition of the amino acid sequence was assessed. Among the conjugates evaluated, compound 16 and 22 presented the highest cytotoxicity (IC50, 0.71 and 0.64 μM respectively), which persisted in the presence of an MTL derived from N-(dialkylaminoalkylenyl)benzamide residue.
- Vivier, Magali,Rapp, Maryse,Galmier, Marie-Josephe,Jarrousse, Anne-Sophie,Miot-Noirault, Elisabeth,Leal, Fernand,Weber, Valérie,Métin, Jacques,Sauzire, Jacques,Chezal, Jean-Michel,Madelmont, Jean-Claude
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supporting information; experimental part
p. 5705 - 5710
(2011/12/21)
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- JAK KINASE MODULATING QUINAZOLINE DERIVATIVES AND METHODS OF USE THEREOF
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Provided herein are quinazoline compounds for treatment of JAK kinase mediated diseases, including JAK2 kinase-, JAK3 kinase- or TYK2 kinase-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions. (I).
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Page/Page column 159
(2010/09/17)
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- Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: Design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition
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A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range.
- Capela, Rita,Oliveira, Rudi,Goncalves, Lidia M.,Domingos, Ana,Gut, Jiri,Rosenthal, Philip J.,Lopes, Francisca,Moreira, Rui
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body text
p. 3229 - 3232
(2010/05/02)
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- DISPIRO TETRAOXANE COMPOUNDS
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A compound having the formula (I) wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; m=any positive integer; n=0-5; X=CH and Y=-C(O)NR1R2, -NR1R2 or -S(O)2R4, where R1, R2 and R4 are each individually selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof, or R1 and R2 are linked so as to form part of a substituted or unsubstituted heterocyclic ring, or X=N and Y=-S(O)2R3 or -C(O)R3, where R3 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.
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Page/Page column 69
(2008/06/13)
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- Cysteine protease inhibitors for use in treatment of IGE mediated allergic diseases
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PCT No. PCT/GB96/01707 Sec. 371 Date Feb. 26, 1998 Sec. 102(e) Date Feb. 26, 1998 PCT Filed Jul. 17, 1996 PCT Pub. No. WO97/04004 PCT Pub. Date Feb. 6, 1997The invention provides compounds for use in the treatment of allergic diseases including juvenile asthma and eczema. The compounds can inhibit IgE mediated reaction to major environmental and occupational allergens and can also have a prophylactic effect against allergic disease by preventing allergic sensitization to environmental and occupational allergens when administered to at-risk individuals (e.g., those at genetic risk of asthma and those exposed to occupational allergens in the workplace). The compounds are also useful for inactivation or attenuation of the allergenicity of allergens in situ. The invention provides compounds and ligands per se, pharmaceutical compositions containing the compounds, processes for producing the compounds and pharmaceutical compositions, and methods for using the compounds and compositions in treatment or prophylaxis of IgE mediated allergic diseases and in inactivation or attenuation of allergens in situ. The invention also enables the reduction or destruction of the viability of allergy-causing organisms.
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- Cycloaddition of N-Buta-1,3-dienyl-succinimide to gem-Substituted Vinyl Phosphonates
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N-Buta-1,3-dienylsuccinimide 3 reacted with trimethyl 2-phosphonoacrylate 4, triethyl 2-phosphonoacrylate 5, α-(diethylphosphono)acrylonitrile 6, α-(diethylphosphono)vinyl methylsulfone 7 and tetraethyl ethenylidene bis(phosphonate) 8 to give the ortho-cy
- Defacqz, Nathalie,Touillaux, Roland,Marchand-Brynaert, Jacqueline
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p. 2273 - 2286
(2007/10/03)
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- Free radical desulfenylation and deselenylation of α-sulfur and α-seleno substituted phosphonates with the n-Bu3SnH/AIBN reagents system.
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Selestive desulfenylation and deselenylation of α-sulfur- and α-seleno-substituted phosphonates under free radical condition are described.Chemoselectivity and scope of title reaction were studied using phosphonates additionaly functionalized in the α-position alkyl, phenyl,ethoxy,chloro,carbonyl and sulfenyl groups.It was found the reduction of a halogen tolerates the presence of the sulfenyl group and the latter could be reduced in the presence of the sulfinyl and sulfonyl moieties.Moreover,one sulfenyl group was selectively removed from α-phosphoryl dithioacetals and the phenylsulphenyl group was reduced preferentially in the presence of the methylsulfenyl one. Key words:Desulfenylation,deselenylation,α-phosphoryl sulfides,α-phosphoryl selenides, tri-n-butyltinhydride,α,α-azaisobutyronitrile.
- Balczewski,Piotr
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p. 113 - 122
(2007/10/03)
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- α-FUNCTIONAL CYCLOALKYLPHOSPHONATES. I. SYNTHESIS
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Cycloalkylphosphonates 2 of different sizes (from cyclopropyl to cycloheptyl) bearing various functional groups Z in α-position were synthesized by bis-alkylation of α-functional methylphosphonates 1 and ω-dibromoalkanes in presence of base.The choice of the basic system is determined by the nature of Z.With powerful electron-withdrawing groups, NaH-THF/DMSO (Method A, for Z = CN, SO2R) or liquid-solid phase transfer process proved to be the more suitable systems.For Z = aryl or SR, lithium diisopropylamide is required to achieve the deprotonation.A wide range of new phoshonates were obtained in high yields on preparative scale.
- Nasser, Jamal,About-Jaudet, Elie,Collignon, Noel
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p. 171 - 179
(2007/10/02)
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- Synthesis and Reactivity of Diethyl (Methylthio)(trimethylsilyl)methylphosphonate
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The title compound is obtained in 80percent yield by silylation of the lithium salt of diethyl 1-methylthiomethylphosphonate.Other approaches involving sulfenylation of diethyl 1-trimethylsilylmethylphosphonate or the Arbuzov reaction of triethyl phosphite with bromo(methylthio)(trimethylsilyl)methane are less efficient.Aldehydes react with the lithium salt of diethyl (methylthio)(trimethylsilyl)methylphosphonate to give the corresponding 1-methylthioethenylphosphonates in good yields (60-85percent) while the reaction with ketones is more complex and Peterson reaction products are formed in very low yields.Methylation, silylation, sulfenylation, and oxidation of the title compound are also described.
- Mikolajczyk, Marian,Balczewski, Piotr
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p. 101 - 106
(2007/10/02)
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- A NEW PROCEDURE FOR OXIDATION OF SULFIDES TO SULFONES
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A series of variously substituted sulfones has been synthesized by oxidation of the corresponding sulfides with the hydrogen peroxide/selenium dioxide system.Very short reaction time, easy work-up and high yields make this new preparation of sulfones a recommendable method.
- Drabowicz, Jozef,Lyzwa, Piotr,Mikolajczyk, Marian
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p. 169 - 172
(2007/10/02)
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