- Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer
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The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H2S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H2S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (1b) was also confirmed on the growth of MC38 tumors in mice.
- Bantzi, Marina,Augsburger, Fiona,Loup, Jérémie,Berset, Yan,Vasilakaki, Sofia,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Szabo, Csaba,Bochet, Christian G.
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p. 6221 - 6240
(2021/05/06)
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- HERBICIDAL CINNOLINIUM COMPOUNDS
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Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides.
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Page/Page column 59
(2020/07/14)
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- CINNOLINIUM COMPOUNDS FOR USE IN A METHOD OF CONTROLLING UNWANTED PLANT GROWTH
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The present invention relates to herbicidally active cinnolinium derivatives of formula (I), as well as to processes and intermediates used for the preparation of such derivatives. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions in controlling undesirable plant growth: in particular the use in controlling weeds, in crops of useful plants.
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Page/Page column 60
(2020/08/28)
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- HERBICIDAL COMPOUNDS
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Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides.
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Page/Page column 53
(2020/08/22)
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- PROSTACYCLIN RECEPTOR AGONIST
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A compound represented by formula (I) or an isomer or a pharmaceutically acceptable salt thereof. The present invention also relates to an application of the same in preparing a drug for treating a disease related to a PGI2 receptor.
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Paragraph 0176-0178
(2020/12/22)
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- Synthetic routes to treprostinil N-acyl methylsulfonamide
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The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacyclin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.
- Brocchini, Steve,Clapp, Lucie H.,Laing, Peter,Picken, Christina,Shen, Lei
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supporting information
(2019/12/25)
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- CRYSTALLINE FORM VI OF SELEXIPAG
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The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof and pharmaceutical compositions thereof.
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Paragraph 00135-00136
(2018/02/28)
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- Selexipag intermediates and method for preparing selexipag
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The invention belongs to the field of chemical preparation, and relates to selexipag intermediates and a method for preparing selexipag. The selexipag intermediates are a compound SLP-4, a compound SLP-7, a compound SLP-8 and a compound SLP-10. The selexipag intermediates and the method have the advantages that the method for preparing the selexipag includes reasonable routes and is low in cost and operative difficulty and little in environmental pollution, raw materials are easily available, accordingly, requirements of large-scale industrial production can be met by the method, and the like.
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Paragraph 0063; 0103; 0104; 0105; 0106; 0107
(2017/08/27)
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- SOLID STATE FORMS OF SELEXIPAG
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The present disclosure relates to solid state forms of Selexipag, in particular selexipag forms IV and V, and processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Paragraph 0095-0096
(2017/03/21)
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- PROCESSES FOR PREPARATION OF SELEXIPAG AND ITS AMORPHOUS FORM
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The present application relates to processes for preparation of Selexipag, its amorphous form, amorphous solid dispersion and pharmaceutical composition thereof. Formula (I):
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Page/Page column 19
(2017/03/14)
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- Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2
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We report a series of inhibitors of secreted phospholipases A2 (sPLA2s) based on substituted indoles, 6,7-benzoindoles, and indolizines derived from LY315920, a well-known indole-based sPLA2 inhibitor. Using the human group X sPLA2 crystal structure, we prepared a highly potent and selective indole-based inhibitor of this enzyme. Also, we report human and mouse group IIA and IIE specific inhibitors and a substituted 6,7-benzoindole that inhibits nearly all human and mouse sPLA 2s in the low nanomolar range.
- Oslund, Rob C.,Cermak, Nathan,Gelb, Michael H.
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supporting information; experimental part
p. 4708 - 4714
(2009/06/06)
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- Gadolinium(III) complexes of dota-derived N-sulfonylacetamides (H 4(dota-NHSO2R) = 10-{2-[(R)sulfonylamino]-2-oxoethyl}-1,4, 7,10-tetraazacyclododecane-1,4,7-triacetic acid): A new class of relaxation agents for magnetic resonance imaging applications
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Four new ligands for lanthanide ions based on the H3do3a (= 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) structure and bearing one N-sulfonylacetamide arm were synthesized, i.e., H4dota-NHSO 2R = 10-{2-[(R)sulfonylamino]-2-oxoethyl}-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acids 1a-e. A 15N-NMR study of the 15N-labelled Eu3+ complex of one such ligands, 1d, showed that the coordination of the N-sulfonylacetamide arm involves the carbonyl O-atom rather than the N-atom. The relaxometric properties of the corresponding Gd3+ complexes were investigated as a function of pH and temperature. These complexes have relaxivities in the range 4.5-5.3 mM -1 s-1, at 20 MHz and 25°, and are characterized by a single H2O molecule in their inner coordination sphere. The mean residence lifetime of this molecule is relatively long (500-700 ns) compared to other anionic complexes. The slow rate of H2O exchange can be justified by the extensive delocalization of the negative charge on the N-sulfonylacetamide arm. The long residence time of the coordinated H 2O allowed the observation of the effect of the prototropic exchange on the relaxivity. The study of the interaction between the complex [Gd(1e)]- and HSA revealed a weak affinity constant highlighting the importance of a localized negative charge on the complex to promote a strong interaction with the protein.
- Aime, Silvio,Botta, Mauro,Cravotto, Giancarlo,Frullano, Luca,Giovenzana, Giovanni B.,Crich, Simonetta Geninatti,Palmisano, Giovanni,Sisti, Massimo
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p. 588 - 603
(2007/10/03)
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- 4-Arylmethyloxymethyl piperidines as tachykinin antagonsits
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The present invention is directed to compounds of the formula (I) STR1 wherein R1, R2, R3, R4, R5, R6, and R7 are defined herein, and pharmaceutically acceptable salts thereof, w
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- Silver halide photographic material
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A novel silver halide photographic material comprising at least one methine compound represented by the following general formula (I): wherein R1 represents -(CH2)r-CONHSO2-R3, -(CH2)s-SO2NHCO-R4, -(CH2)t-CONHCO-R5 or -(CH2)u-SO2NHSO2-R6 in which R3, R4, R5 and R6 each represents an alkyl group, alkoxy group or amino group, r, s, t and u each represents an integer 1 to 5, and R2 represents has the same meaning as R1 or represents an alkyl group; Z1 and Z2 each represents a nonmetallic atom group required to form a 5- or 6-membered heterocyclic group; p and q each represents an integer 0 or 1; L1, L2 and L3 each represents a methine group; m represents an integer 0 to 2; X represents an anion; and k represents an integer required to adjust the charge in the molecule to 0. The silver halide photographic material may comprise at least one methine compound represented by the general formula (I) and at least one water-soluble dye.
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