- Ferulic acid amide derivatives with varying inhibition of amyloid-β oligomerization and fibrillization
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized, in part, by the misfolding, oligomerization and fibrillization of amyloid-β (Aβ). Evidence suggests that the mechanisms underpinning Aβ oligomerization and subsequent fibrillization are distinct, and may therefore require equally distinct therapeutic approaches. Prior studies have suggested that amide derivatives of ferulic acid, a natural polyphenol, may combat multiple AD pathologies, though its impact on Aβ aggregation is controversial. We designed and synthesized a systematic library of amide derivatives of ferulic acid and evaluated their anti-oligomeric and anti-fibrillary capacities independently. Azetidine tethered, triphenyl derivatives were the most potent anti-oligomeric agents (compound 2i: IC50 = 1.8 μM ± 0.73 μM); notably these were only modest anti-fibrillary agents (20.57% inhibition of fibrillization), and exemplify the poor correlation between anti-oligomeric/fibrillary activities. These data were subsequently codified in an in silico QSAR model, which yielded a strong predictive model of anti-Aβ oligomeric activity (κ = 0.919 for test set; κ = 0.737 for validation set).
- Kolaj, Igri,Wang, Yanfei,Ye, Kailin,Meek, Autumn,Liyanage, S. Imindu,Santos, Clarissa,Weaver, Donald F.
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supporting information
(2021/07/07)
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- Carbonyl azetidine substituted naphthalimide fluorescent dye as well as synthesis method and application thereof
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The invention provides a novel carbonyl azetidine substituted naphthalimide fluorescent dye as well as synthesis and application thereof. The dye takes 1, 8-naphthalimide as a fluorophore parent, and the fourth site of the 1, 8-naphthalimide is covalently connected with carbonyl azetidine. The novel fluorescent dye has excellent fluorescence intensity and light stability, so that the novel fluorescent dye has wide application prospects in the fields of fluorescence detection, fluorescence imaging and the like, especially in the emerging fields of single molecule detection, super-resolution fluorescence imaging and the like. R1 is H, C1-4 alkyl and aryl, R2 is shown in the specification, and in R2, X1 is H, C1-2 alkyl, X2 is C1-2 alkyl or shown in the specification, X3 is C1-2 alkyl or shown in the specification, and X4 is C1-2 alkyl.
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Paragraph 0097-0101
(2021/06/13)
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- Carbonyl azetidine substituted coumarin fluorescent dye as well as synthesis method and application thereof
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The invention provides a novel carbonyl azetidine substituted coumarin fluorescent dye as well as synthesis and application thereof. The structural innovation of the dye is that carbonyl azetidine is covalently linked to the No.7 site of a coumarin parent. The novel fluorescent dye has excellent fluorescence intensity and light stability, so that the novel fluorescent dye has wide application prospects in the fields of fluorescence detection, fluorescence imaging and the like, especially in the emerging fields of single molecule detection, super-resolution fluorescence imaging and the like. R1 is C1-4 alkyl, and R2 is shown in the specification, X1 is H or C1-2 alkyl, X2 is C1-2 alkyl or shown in the specification, X3 is C1-2 alkyl or shown in the specification, and X4 is C1-2 alkyl.
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Paragraph 0065-0069
(2021/06/12)
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- Carbonyl azetidine substituted NBD fluorescent dye as well as synthesis method and application thereof
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The invention provides a novel carbonyl azetidine substituted NBD fluorescent dye as well as synthesis and application thereof. The structure of the dye is characterized in that carbonyl azetidine is covalently connected to the fourth site of a 4-chloro-7-nitrobenzene-2-oxa-1, 3-diazole (NBD) parent. The novel fluorescent dye has excellent fluorescence intensity and light stability, so that the novel fluorescent dye has wide application prospects in the fields of fluorescence detection, fluorescence imaging and the like, especially in the emerging fields of single molecule detection, super-resolution fluorescence imaging and the like. R1 is as described in the specification, X1 is H or C1-2 alkyl, X2 is C1-2 alkyl or as described in the specification, x3 is C1-2 alkyl or as described in the specification, and X4 is C1-2 alkyl.
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Paragraph 0059-0063
(2021/06/12)
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- CASPASE INHIBITOR AND PHARMACEUTICAL COMPOSITION, USE AND THERAPEUTIC METHOD THEREOF
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Disclosed are a class of compounds as a caspase inhibitor, and in particular the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound in treating caspase-related diseases.
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Paragraph 0085; 0086
(2019/04/05)
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- PROCESS FOR THE PREPARATION OF 2-(3-(FLUOROMETHYL)AZETIDIN-1-YL)ETHAN-1-OL
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Methods of making 2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol 9, an intermediate useful for the synthesis of estrogen receptor modulating compounds are described.
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Page/Page column 19
(2018/07/05)
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- Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases
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The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).
- Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Komiya, Takaki,Hagiya, Hiroshi,Mizuno, Hirotaka,Shioya, Hiroki,Ono, Takeji,Takada, Yuka,Maeda, Tatsuo,Matsunaga, Norikazu,Kondo, Tetsu,Tominaga, Sachiko,Nunoya, Ken-Ici,Kiyoshi, Hidekazu,Komeno, Masaharu,Nakade, Shinji,Habashita, Hiromu
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p. 9508 - 9530
(2017/12/26)
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- HETERO-HALO INHIBITORS OF HISTONE DEACETYLASE
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This invention provides compounds that are inhibitors of HDAC2. The compounds (e.g., compounds according to Formula I, II or any of Compounds 100-128 or any of those in Tables 2 or 3) accordingly are useful for treating, alleviating, or preventing a condition in a subject such as a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, or neoplastic disease, or for improving memory or treating, alleviating, or preventing memory loss or impairment.
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Paragraph 466
(2017/01/26)
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- MONOBACTAMS
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The present invention is directed to a new class of monobactam derivatives and their use for treating bacterial infections.
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Page/Page column 55-56
(2012/06/16)
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- Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold
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Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P 3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P 3 and in vivo PLL activity in mice.
- Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Tokuda, Natsuko,Takada, Yuka,Shioya, Hiroki,Mizuno, Hirotaka,Komiya, Takaki,Ono, Takeji,Hagiya, Hiroshi,Minami, Masashi,Nakade, Shinji,Habashita, Hiromu
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scheme or table
p. 144 - 148
(2012/02/16)
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- Azetidine derivatives as novel γ-aminobutyric acid uptake inhibitors: Synthesis, biological evaluation, and structure-activity relationship
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In this study azetidine derivatives representing conformationally constrained GABA or β-alanine analogs were evaluated for their potency as GABA-uptake inhibitors. The study comprised derivatives substituted in 2- as well as in 3-position with either an acetic acid moiety or a carboxylic acid function. In addition, azetidine derivatives bearing a tetrazole ring as a bioisosteric substitute for a carboxylic acid group were included. 3-Hydroxy-3-(4-methoxyphenyl)azetidine derivatives were explored as analogs of the known GABA-uptake inhibitor NNC-05-2045 exhibiting an azetidine ring instead of a piperidine ring present in the latter. Both, N-unsubstituted compounds as well as their N-alkylated lipophilic derivatives, were biologically evaluated for their affinity to the GAT-1 and GAT-3 transporters. Azetidin-2-ylacetic acid derivatives provided with a 4,4-diphenylbutenyl or 4,4-bis(3-methyl-2-thienyl)butenyl moiety as lipophilic residue were found to exhibit the highest potency at GAT-1 with IC50 values of 2.83 ± 0.67 μM and 2.01 ± 0.77 μM, respectively. The most potent GAT-3 inhibitor among these compounds appeared to be the β-alanine analog 1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}azetidine-3-carboxylic acid (12d) displaying an IC50 value of 15.3 ± 4.5 μM. Whereas the tetrazole derivatives showed no potency as GABA-uptake inhibitors, the 3-hydroxy-3-(4-methoxyphenyl)azetidine derivatives exhibited moderate affinity to GAT-1 (compound 18b: IC50 = 26.6 ± 3.3 μM) and to GAT-3 (compound 18e: IC50 = 31.0 ± 4.7 μM).
- Faust, Mark R.,H?fner, Georg,Pabel, J?rg,Wanner, Klaus T.
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experimental part
p. 2453 - 2466
(2010/07/08)
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- PYRAZOLE-I, 2, 4 -OXAD IAZOLE DERIVATIVES AS S.PHING0SINE-1-PH0SPHATE AGONISTS
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Disclosed are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is zero or an integer selected from 1 through 4; R1 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with one to five substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, benzyl, OR4, and/or halogen; and R2, R3, R4, and n are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
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Page/Page column 43-44
(2010/08/08)
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- AZETIDINES AND CYCLOBUTANES AS HISTAMINE H3 RECEPTOR ANTAGONISTS
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The invention relates to compounds of formula (I) wherein R, R0, R1, m, n and X1 to X4 have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.
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Page/Page column 150
(2010/01/29)
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- SPIRO CYCLOPENTANE COMPOUNDS USEFUL AS ANTAGONISTS OF THE H1-RECEPTOR
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This invention relates to novel spiro cyclopentane derivatives of formula (I) or a pharmaceutically acceptable salt thereof, for treating diseases and conditions of the central nervous system (CNS), in particular sleep disorders.
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Page/Page column 50
(2009/03/07)
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- NOVEL PYRIDINE DERIVATIVE AND PYRIMIDINE DERIVATIVE (3)
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A compound represented by the following formula, a salt thereof or a hydrate of the foregoing has an excellent hepatocyte growth factor receptor (HGFR) inhibitory activity, and exhibits anti-tumor activity, angiogenesis inhibitory activity and cancer metastasis inhibitory activity. [R1 represents a 3- to 10-membered non-aromatic heterocyclic group or the like; R2 and R3 represent hydrogen; R4, R5, R6, and R7 may be the same or different and each represents hydrogen, halogen, C1-6 alkyl or the like; R8 represents hydrogen or the like; R9 represents a 3- to 10-membered non-aromatic heterocyclic group or the like; n represents an integer of 1 or 2; X represents -CH=, nitrogen or the like.]
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Page/Page column 80
(2008/06/13)
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- Process for preparing phenoxypyridine derivatives
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A process for preparing a compound represented by the formula (I): comprising reacting a compound represented by the formula (II) or salt thereof: with a compound represented by the formula (III): in the presence of a condensation reagent, wherein R1 represents 1) optionally substituted azetidin-1-yl, 2) optionally substituted pyrrolidin-1-yl, 3) optionally substituted piperidin-1-yl, etc.; R2, R3, R4 and R5 may be the same or different and each represents hydrogen or fluorine; and R6 represents hydrogen or fluorine.
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Page/Page column 14-15
(2008/12/08)
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- AMINOCARBOXYLIC ACID DERIVATIVE AND MEDICINAL USE THEREOF
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The present invention relates to a compound represented by the formula (I), a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, and a medicament containing the same. The compound represented by the formula (I) has an ability to bind to an S1P receptor (particularly, EDG-1, EDG-6, and/or EDG-8) and is useful for preventing and/or treating for rejection to transplantation, graft-versus-host disease, autoimmune diseases, allergic diseases, neurodegenerating diseases, and the like. wherein all symbols are described in the specification.
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- COMPOUNDS, COMPOSITIONS CONTAINING THEM, PREPARATIONS THEREOF AND USES THEREOF II
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Compounds of Formulae I, or pharmaceutically acceptable salts thereof: (I) wherein R1, R2, R3, R4 and G are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
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Page/Page column 68
(2010/10/20)
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- AMINOCARBOXYLIC ACID DERIVATIVE AND MEDICINAL USE THEREOF
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A compound represented by the general formula (I), a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug of any of these; and a drug containing any of these. (I) (In the formula, all the symbols are as defined in the description.) The compound represented by the general formula (I) has the ability to combine with an S1P receptor (especially EDG-1, EDG-6, and/or EDG-8). It is useful for the prevention and/or treatment of rejection reactions to transplantation, graft versus host diseases, autoimmune diseases, allergic diseases, neurodegenerative diseases, etc.
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Page/Page column 126
(2008/06/13)
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- PHENYL ACETAMIDES
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The invention relates to the phenyl acetamides of formula (I), to a method for producing them and to their use for producing drugs for use in the treatment and/or prophylaxis of human or animal diseases, especially cardiovascular diseases.
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Page/Page column 35-36
(2010/02/14)
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- Inhibitors of human glycogen phosphorylase
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The present invention is directed to a novel binding site for a glycogen phosphorylase inhibitor found within a glycogen phosphorylase enzyme. The novel binding site allows the design novel of glycogen phosphorylase inhibitors.
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- N-L-seryl-3-azetidinecarboxylic acid
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N-L-seryl-3-azetidinecarboxylic acid, useful for sterilizing the male parts of plants.
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