- Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore
-
Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher’s disease and has been suggested as a potential target for treating Parkinson’s disease. Herein, we report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with T-036. The ring opening of T-036 resulted in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, we discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.
- Daini, Masaki,Fujii, Takahiro,Ikeda, Zenichi,Inazuka, Masakazu,Kakegawa, Keiko,Kasahara, Takahito,Kikuchi, Fumiaki,Kimoto, Kouya,Kohara, Hiroshi,Mikami, Satoshi,Murakami, Masataka,Nakamura, Minoru,Oak, Jeong-Ho,Ohashi, Tomohiro,Oki, Hideyuki,Puenner, Florian,Sasaki, Minoru,Sato, Sho,Seto, Masaki,Suzaki, Tomohiko,Takai, Yuichi,Takami, Kazuaki,Tanaka, Yuta,Wada, Yasufumi,Wang, Junsi,Yamamoto, Takeshi
-
p. 4270 - 4290
(2022/03/14)
-
- 3-3 - diarylacrylate/amide compound containing triaryl phosphonium salt as well as preparation method and application thereof
-
The invention discloses I-3-diaryl acrylate/amide sterilization compounds of triarylphosphonium salts shown 3 . The compound of the formula I, which is an active ingredient, has a high activity in prevention and control of pathogenic bacteria in crops, horticulture, and vegetables, and can exhibit an excellent control effect even at a low dose, and has a wide control spectrum.
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Paragraph 0121
(2021/10/05)
-
- Amide compound as well as preparation method and application thereof
-
The invention provides an amide compound as well as a preparation method and application thereof. The amide compound has a structure as shown in a formula I in the specification. The amide compound disclosed by the invention can have high insecticidal act
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-
Paragraph 0218; 0223-0225
(2021/04/17)
-
- AMIDE COMPOUNDS AND PREPARATION METHOD THEREFOR AND USE THEREOF
-
Provided are amide compounds and a preparation method therefor and the use thereof. The amide compounds have a structure represented by formula (I). The amide compounds of the present invention have high insecticidal activity at a low dosage and have a go
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Page/Page column 30
(2021/04/23)
-
- Synthesis of N-trifluoromethyl amides from carboxylic acids
-
Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
-
supporting information
p. 2245 - 2255
(2021/08/12)
-
- FARNESOID X RECEPTOR AGONISTS AND USES THEREOF
-
Described herein are compounds that are farnesoid X receptor agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity.
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Paragraph 00462
(2020/04/25)
-
- CRBN LIGANDS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of CRBN, and the treatment of CRBN-mediated disorders.
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-
Paragraph 00462-00464
(2019/08/20)
-
- TETRAHYDROISOQUINOLINE DERIVED PRMT5-INHIBITORS
-
A compound of formula I wherein: n is 1 or 2: p is 0 or 1; R1 is optionally one or more halo or methyl groups; R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2c and R2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R3a and R3b are independently selected from H and Me; R4 is either H or Me; R5 is either H or Me; R6a and R6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C5-12 heteroaryl.
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Page/Page column 102
(2016/03/19)
-
- 18F LABELLED THIAZOLYLHYDRAZONE DERIVATIVES
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The present invention relates to compounds of Formula (I) wherein R1 and R2 are independently selected from 19F and 18F having selective binding for MAO-B as compared with MAO-A. The invention also provides radi
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Page/Page column 10-11
(2016/07/05)
-
- New anti-invasive compounds
-
The present invention relates to a compound of formula (I): wherein A and A' independently represent a phenylene group or a pyridylene group; R2 is a hydrogen atom or a (C1-C4)alkyl group; R3 is a 2-pyridyl grou
- -
-
Paragraph 0091
(2014/05/06)
-
- NOVEL SPIROINDOLINE COMPOUNDS
-
This invention relates to novel spiroindoline compounds of formula (I) that are generally useful as medicaments, more specifically as medicaments for animals. The medicament can preferably be used for the treatment of helminth infections and the treatment of parasitosis, such as caused by helminth infections. This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to animals in need of the treatments. This invention also relates to the preparation of said compounds. Moreover this invention relates to pharmaceutical compositions and kits comprising the compounds.
- -
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Paragraph 216
(2013/03/26)
-
- Spirocyclic dihydropyridines by electrophile-induced dearomatizing cyclization of N-alkenyl pyridinecarboxamides
-
On treatment with acylating or sulfonylating agents, N-alkenyl pyridine carboxamides (N-pyridinecarbonyl enamines) undergo a dearomatizing cyclization initiated by pyridine acylation and followed by intramolecular trapping of the resulting pyridinium cation. The products are spirocyclic dihydropyridines which may be further elaborated to spirocyclic heterocycles with drug-like features.
- Senczyszyn, Jemma,Brice, Heloise,Clayden, Jonathan
-
supporting information
p. 1922 - 1925
(2013/06/04)
-
- Phenylalanine derivatives as GPR142 agonists for the treatment of Type II diabetes
-
GPR142 is a novel GPCR that is predominantly expressed in pancreatic β-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.
- Du, Xiaohui,Kim, Yong-Jae,Lai, Sujen,Chen, Xi,Lizarzaburu, Mike,Turcotte, Simon,Fu, Zice,Liu, Qingxiang,Zhang, Ying,Motani, Alykhan,Oda, Kozo,Okuyama, Ryo,Nara, Futoshi,Murakoshi, Michiko,Fu, Angela,Reagan, Jeff D.,Fan, Peter,Xiong, Yumei,Shen, Wang,Li, Leping,Houze, Jonathan,Medina, Julio C.
-
p. 6218 - 6223
(2012/10/29)
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- SUBSTITUTED BENZENE COMPOUNDS
-
The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.
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Page/Page column 426
(2012/11/06)
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- S PIROINDOLINE COMPOUNDS FOR USE AS ANTHELMINTHI CS
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This invention relates to spiroindoline compounds for the treatment of helminth infections and the treatment of parasitosis, such as caused by helminth infections. This invention also relates to uses of the compounds to make medicaments and treatments com
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Page/Page column 37
(2011/09/14)
-
- Design, synthesis, and biological evaluation of chromone-based p38 MAP kinase inhibitors
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3-(4-Fluorophenyl)-2-(4-pyridyl)chromone derivatives were synthesized and evaluated as p38 MAP kinase inhibitors. Introduction of an amino group in the 2-position of the pyridyl moiety gave p38α inhibitors with IC50 in the low nanomolar range (
- Dyrager, Christine,M?llers, Linda Nilsson,Kj?ll, Linda Karlsson,Alao, John Patrick,Dinér, Peter,Wallner, Fredrik K.,Sunnerhagen, Per,Gr?til, Morten
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supporting information; experimental part
p. 7427 - 7431
(2011/12/16)
-
- PTERIDINES AND THEIR USE AS AGROCHEMICALS
-
The present disclosure relates to 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and their use as agrochemicals and animal health products.
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Page/Page column 62
(2011/04/14)
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- INSECTICIDAL COMPOUNDS
-
A compound of formula (I) wherein A, p, R1, R3, R4, R5, and R8 are as defined in claim 1. Furthermore, the present invention relates to intermediates used to prepare compounds of formula (I), to metho
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Page/Page column 30-31
(2011/02/24)
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- INSECTICIDAL PHENYL- OR PYRIDYL-PIPERIDINE COMPOUNDS
-
A compound of formula (I): wherein A, p, R1, R3, R4, R5, R6, m, R7, n and R8 are as defined in claim 1. Furthermore, the present invention relates to intermediates used to prepar
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Page/Page column 31-32
(2010/04/03)
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- NEW COMPOUNDS 574
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The present invention relates to novel compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Downs syndrome,
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Page/Page column 24
(2010/06/13)
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- AMIDE COMPOUND AND METHOD FOR CONTROLLING PLANT DISEASE USING THE SAME
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Disclosed is a plant disease control agent containing an amide compound represented by formula (1) below which has an excellent plant disease controlling effect as an active ingredient. (In the formula, X1, X2, Z1 and Esu
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-
Page/Page column 29-30
(2010/04/30)
-
- PHENYLALANINE AMIDE DERIVATIVES USEFUL FOR TREATING INSULIN-RELATED DISEASES AND CONDITIONS
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Provided herein are compounds of formula I: wherein A, B, X, R1 , R2 and subscript n are as defined in the following disclosure. Compositions comprising the compounds are also provided, as well as methods for their use, for example, in treatment of type 2 diabetes and type 2 diabetes-related conditions
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Page/Page column 50
(2010/09/03)
-
- 4-Substituted 1-acyloxypyridine-2(1H)-thiones: Experimental and computational studies of the substituent effect on electronic absorption spectra
-
(Chemical Equation Presented) A series of eight 4-substituted 1-(adamantane-1-carbonyloxy)pyridine-2(1H)-thiones (1, X=H, OC7H 15, Me, CF3, SC3H7, CN, COOMe, and Cl) was prepared and characterized by UV-vis spectroscopy in MeCN and cyclohexane. The observed lowest energy transition, designated as πCS→ π*ring, exhibits a substantial substituent effect and λmax ranges from 333 (X=OC 7H15) to 415 nm (X=CN). Experimental λ max values for all esters except for 1b (X=OC7H 15) correlate with the σp - parameter (ρ = 0.41 ± 0.03, r2= 0.95). In contrast, the energy of the absorption band at about 295 nm, designated as πCS → π*CS, is practically substituent independent. Both absorption bands exhibit a modest negative solvatochromic effect. The experimental absorption energies correlate better with excitation energies calculated for N-acetyloxy analogues 2 with the ZINDO//DFT than with the TD-DFT//DFT method. Calculations for a series of 12 N-acetates 2 predict the most blueshifted π → π* transition for the alkoxy substituent and most red-shifted for the NO2 group relative to the parent 2a (X = H). 2009 American Chemical Society.
- Jankowiak, Aleksandra,Kaszynski, Piotr
-
supporting information; experimental part
p. 7441 - 7448
(2010/01/16)
-
- INSECTICIDAL COMPOUNDS
-
A compound of formula (I): wherein R1 is pyrid-4-yl optionally substituted by one to four substituents independently selected from halogen, C1-3 alkyl or C1-3 haloalkyl; R2 is hydrogen, halogen, C1-4
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Page/Page column 19
(2009/12/23)
-
- ORGANIC COMPOUNDS
-
The present invention provides heterocyclicderivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.
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Page/Page column 64
(2010/01/30)
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- HETEROCYCLIC CYTOKINE INHIBITORS
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The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory, anti-pain or anti-cancer agents. There are further provided m
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Page/Page column 132
(2010/11/27)
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- ISOQUINOLINE DERIVATIVES AND THEIR USE AS INHIBITORS OF CYTOKINE MEDIATED DISEASES
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The invention concerns a compound of formula (I) or pharmaceutically-acceptable salts thereof wherein R1, R2, R3, R4, R5 and m are as defined in the specification, processes for their preparation, pha
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Page/Page column 59-60
(2008/06/13)
-
- Synthesis of methylene- and difluoromethylenephosphonate analogues of uridine-4-phosphate and 3-deazauridine-4-phosphate
-
(Chemical Equation Presented) Cytidine triphosphate synthetase (CTPS) catalyzes the formation of cytidine triphosphate from glutamine, uridine-5′-triphosphate (UTP), and adenosine-5′-triphosphate. Inhibitors of CTPS are of interest because of their potential as therapeutic agents. One approach to potent enzyme inhibitors is to use analogues of high energy intermediates formed during the reaction. The CTPS reaction proceeds via the high energy intermediate UTP-4-phosphate (UTP-4-P). Four novel analogues of uridine-4-phosphate (U-4-P) and 3-deazauridine-4-phosphate (3-deazaU-4-P) were synthesized in which the labile phosphate ester oxygen was replaced with a methylene and difluoromethylene group. The methylene analogue of U-4-P, compound 1, was prepared by a reaction of the sodium salt of tert-butyl diethylphosphonoacetate with protected, 4-O-activated uridine followed by acetate deprotection and decarboxylation. It was found that this compound undergoes relatively facile dephosphonylation presumably via a metaphosphate intermediate. The difluoromethylene derivative, compound 2, was prepared by electrophilic fluorination of protected 1. This compound was stable and did not undergo dephosphonylation. Synthesis of the methylene analogue of 3-deazaU-4-P, compound 3, was achieved by ribosylation of protected 4-(phosphonomethyl)-2- hydroxypyridine. Electrophilic fluorination was also employed in the preparation of protected 4-(phospho-nodifluoromethyl)-2-hydroxypyridine which was used as the key building block in the synthesis of difluoro derivative 4. These compounds represent the first examples of a nucleoside in which the base has been chemically modified with a methylene or difluormethylenephosphonate group.
- Taylor, Scott D.,Mirzaei, Farzad,Sharifi, Ali,Bearne, Stephen L.
-
p. 9420 - 9430
(2007/10/03)
-
- Novel scaffolds for beta-helix mimicry
-
Functionalized pyridazine derivatives having a low molecular weight and pharmaceutical compositions thereof are useful as alpha-helix mimetics and for treating conditions and/or disorders mediated by alpha-helix-binding receptors and proteins.
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Page/Page column 31
(2008/06/13)
-
- NOVEL PROCESSES FOR THE PRODUCTION OF USEFUL INTERMEDIATES
-
The present application relates to a new process for the asymmetric production of 3-(pyridin-4-yl)-3-hydroxy-pentanoic acid derivatives, which are useful intermediates in the manufacture of compounds that are known to show antiproliferative activity.
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Page/Page column 36
(2008/06/13)
-
- FUROISOQUINOLINE DERIVATIVE AND USE THEREOF
-
The present invention provides a compound represented by the formula ???wherein A represents (1) a bond, (2) a group represented by the formula -CRa=CRb- (Ra and Rb each represent a hydrogen atom or C1-6 alkyl) and the like; R1 represents (1) cyano or (2) an optionally esterified or amidated carboxyl group; R2 represents(1) a hydrogen atom, (2) an optionally substituted hydroxy group,(3) an optionally substituted amino group and the like; R3 and R4 each represent a hydrogen atom and the like; R5 represents a hydrogen atom and the like; R6 represents an optionally substituted hydroxy group and the like; R7and R8 each represent an optionally substituted hydrocarbon group and the like; R9 and R10 each represent (1) a hydrogen atom and the like; Y represents an optionally substituted methylene group; and n represents 0 or 1, or a salt thereof, which has an excellent phosphodiesterase IV inhibiting action.
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Page/Page column 75
(2010/02/11)
-
- Phenylalanine derivatives
-
Phenylalanine derivatives of formula (1) are described: wherein L1 is a linker atom or group;X1 is a group selected from —N(R3)CO—, —N(R3)SO2—, —N(R3)C(O)O— or—N(R3)CON(R3a
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Page/Page column 18-19
(2010/02/12)
-
- CYCLIC COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
-
The invention provides a novel class of cyclic compounds, pharmaceutical compositions comprising such cyclic compounds and methods of using such compounds to treat or prevent diseases and disorders associated with cyclin-dependent kinases (CDKs) activity,
- -
-
-
- SUBSTITUTED TRIAZINE KINASE INHIBITORS
-
The present invention provides substituted 1,3,5-triazine compounds as kinase inhibitors and a method for treating or ameliorating a kinase mediated disorder.
- -
-
-
- Benzothiazole derivatives with activity as adenosine receptor ligands
-
The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.
- -
-
-
- Nitrogenous heterocyclic derivatives and medicine thereof
-
The present invention provides a novel nitrogen-containing heterocyclic compound useful as a phosphodiesterase-4 inhibitor, and a medicament comprising the same. Further, the present invention provides a nitrogen-containing heterocyclic compound represented by the following formula, its salt or hydrates thereof, and a medicament comprising the same. wherein the ring A is an aromatic hydrocarbon ring which may have a heteroatom, the ring B represents (a) a saturated hydrocarbon ring, (b) an unsaturated hydrocarbon ring, (c) a saturated heterocyclic ring or (d) an unsaturated heterocyclic ring, all of which may have a substituent group.
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-
Page column 48
(2008/06/13)
-
- Bis-acyloxymethyl derivatives
-
This invention relates to new pyridyl, quinoline and acridine bis-acyloxymethyl compounds; to compositions comprising these compounds; and to processes for their utility as fungicides, bactericides and as inhibitors of the growth of cancer in warm-blooded animals. In accordance with this invention, new bis-acyloxymethyl derivatives are provided of the formula: STR1 wherein B is selected from substituted and unsubstituted alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl and alkynyl; A is selected from hydrogen and B; or, A and B together comprise a pyrrolizine; L is selected from STR2 wherein Y is selected from hydrogen or STR3 each R and Z is independently selected from hydrogen or substituted and unsubstituted alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, alkynyl, amine group, each Z' is independently selected from hydrogen and substituted or unsubstituted alkyl; M is Z or is selected from halogen, nitro, hydroxyl, nitrile and substituted or unsubstituted, carboxylic acid group, carboxylic acid ester group, carboxylic acid amide group, sulfonic acid group and sulfonic acid amide group; ether group, thioether group, acylated hydroxyl, sulfonylamide, sulfonylurea, sulfoxide group, sulfone group and mixtures thereof; each n is the same and is 0 or 1; q is from 0-4; and, X is the anion of an acid.
- -
-
-
- Synthesis, Chemistry, and Antineoplastic Activity of α-Halopyridinium Salts: Potential Pyridone Prodrugs of Acylated Vinylogous Carbinolamine Tumor Inhibitors
-
A series of 4- and 5-methyl>-1H-pyrrolizin-5-yl>-2-halopyridinium iodides were synthesized.The rates of hydrolysis of the α-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer composition, and ionic strength.The 4- and 5-pyrrolizinyl-2-halopyridinium iodides and the corresponding pyridones were evaluated against P388 lymphocytic leukemia in vivo.The α-fluoropyridinium compounds were active but the α-chloro compounds were not.This activity was correlated with the rates of hydrolysis of the α-halopyridinium compounds to the active pyridone.Compounds that were active in the P388 screen were evaluated in L1210 leukemia, M5076 carcinoma, and MX-1 mammary xenograft assays in mice.
- Anderson, Wayne K.,Dean, Dennis C.,Endo, Toshiyasu
-
p. 1667 - 1675
(2007/10/02)
-
- 2-halo-pyridines
-
2-Halo-pyridines of the general formula I STR1 wherein X is Cl or Br; A is =0 or STR2 Ar is phenyl or substituted phenyl of the general formula STR3 in which n is 0, 1, 2 or 3; R is alkyl C1-4, alkoxy C1-4, phenoxy, alkylthio C1-4, halogen especially F and Cl, OH or C6 H5 ; and their salts, addition compounds and precursors (prodrugs). Furthermore the invention is directed to the production of these compounds and pharmaceuticals containing them.
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