- Design, synthesis, and biological evaluation of novel FXR agonists based on auraptene
-
Farnesoid X receptor (FXR) has been considered as an attractive target for metabolic disorder and liver injury, while many current FXR agonists suffer from undesirable side effects, such as pruritus. Therefore, it is urgent to develop new structure types different from current FXR agonists. In this study, a series of structural optimizations were introduced to displace the unstable coumarin and geraniol scaffolds of auraptene (AUR), a novel and safe FXR agonist. All of these efforts led to the identification of compound 14, a potent FXR agonist with nearly fourfold higher activity than AUR. Molecular modeling study suggested that compound 14 fitted well with binding pocket, and formed the key ionic bond with His291 and Arg328. In acetaminophen-induced acute liver injury model, compound 14 exerts better therapeutic effect than that of AUR, which highlighting its pharmacological potential in the treatment of drug-induced liver injury.
- Qiu, Qianqian,Wang, Yanjuan,Gu, Guolong,Yu, Fan,Zhang, Shichao,Zhao, Yining,Ling, Bai
-
-
- Imatinib intermediate and preparation method thereof (by machine translation)
-
The invention discloses an imatinib intermediate and a preparation method thereof. The structure of the imatinib intermediate is as shown in the formula, wherein R is C. 1 - C4 Alkyl. The preparation method of the imatinib intermediate is simple and easy to obtain, simple and convenient to operate, high in yield and low in production cost, is suitable for large-scale industrial production, and has great economic and social benefits. (by machine translation)
- -
-
Paragraph 0154-0156
(2020/07/03)
-
- Synthesis and Absolute Configuration of Habiterpenol
-
The synthesis of habiterpenol, a G2 checkpoint inhibitor, was achieved through the stereoselective Ti(III)-mediated radical cyclization of a β-epoxide as the key reaction. Moreover, the absolute configuration of habiterpenol was determined.
- Konya, Miyuki,Shimoyama, Kenta,Arima, Shiho,Fukuda, Takashi,Uchida, Ryuji,Tomoda, Hiroshi,Nagamitsu, Tohru
-
supporting information
p. 5131 - 5134
(2020/07/04)
-
- Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
-
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
- Song, Lijun,Merceron, Romain,Gracia, Bego?a,Quintana, Ainhoa Lucía,Risseeuw, Martijn D. P.,Hulpia, Fabian,Cos, Paul,Aínsa, José A.,Munier-Lehmann, Hélène,Savvides, Savvas N.,Van Calenbergh, Serge
-
p. 2753 - 2775
(2018/04/23)
-
- Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine
-
We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.
- Monjas, Leticia,Swier, Lotteke J. Y. M.,Setyawati, Inda,Slotboom, Dirk J.,Hirsch, Anna K. H.
-
supporting information
p. 1693 - 1696
(2017/10/27)
-
- Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid
-
Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
- Krogsgaard-Larsen, Niels,Delgar, Claudia G.,Koch, Karina,Brown, Patricia M. G. E.,M?ller, Charlotte,Han, Liwei,Huynh, Tri H. V.,Hansen, Stinne W.,Nielsen, Birgitte,Bowie, Derek,Pickering, Darryl S.,Kastrup, Jette Sandholm,Frydenvang, Karla,Bunch, Lennart
-
p. 441 - 457
(2017/04/26)
-
- Regioselective Enzymatic Carboxylation of Bioactive (Poly)phenols
-
In order to extend the applicability of the regioselective enzymatic carboxylation of phenols, the substrate scope of o-benzoic acid (de)carboxylases has been investigated towards complex molecules with an emphasis on flavouring agents and polyphenols possessing antioxidant properties. o-Hydroxycarboxylic acid products were obtained with perfect regioselectivity, in moderate to excellent yields. The applicability of this method was proven by the regioselective bio-carboxylation of resveratrol on a preparative scale with 95% yield. (Figure presented.).
- Plasch, Katharina,Resch, Verena,Hitce, Julien,Pop?oński, Jaros?aw,Faber, Kurt,Glueck, Silvia M.
-
supporting information
p. 959 - 965
(2017/03/27)
-
- Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging
-
Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme’s aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3β inhibitors. Radiosynthesis of a potential GSK-3β tracer [18F]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [18F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted.
- Hu, Kongzhen,Patnaik, Debasis,Collier, Thomas Lee,Lee, Katarzyna N.,Gao, Han,Swoyer, Matthew R.,Rotstein, Benjamin H.,Krishnan, Hema S.,Liang, Steven H.,Wang, Jin,Yan, Zhiqiang,Hooker, Jacob M.,Vasdev, Neil,Haggarty, Stephen J.,Ngai, Ming-Yu
-
supporting information
p. 287 - 292
(2017/03/17)
-
- Facile synthesis of 2-aryl or β,γ-unsaturated esters via 1,2-Migration from aryl or α,β-unsaturated ketones using thallium(III) p-tosylate
-
The experiment reports that 2-aryl esters can be efficiently synthesized via 1,2-aryl migration from aryl ketones using thallium(III) p-tosylate in high yields. To determine optimum conditions for conversion of aryl ketones to 2-aryl esters, the effects of solvents were examined. An initial reaction of 4'-methoxypropiophenone and perchloric acid using thallium(III) p-tosylate in ethanol afforded ethyl 2-(4-methoxyphenyl)propanoate in only 10% yield after 24 h at room temperature. However, the corresponding reaction in ethanol/triethyl orthoformate (4/1) was completed in 1 h between 0 °C and room temperature to give ethyl 2-(4-methoxyphenyl)propanoate in 94% yield. The presence of triethyl orthoformate induced rapid ketalization of enol intermediate and facilitated 1,2-migration of the 4-methoxyphenyl group. The relative effectiveness of several metal salts was also examined for conversion of 2',4'-dimethoxypropiophenone to ethyl 2-(2,4-dimethoxyphenyl)propanoate. The solvents were evaporated off under reduced pressure, and the residue was dissolved in methylene chloride. The white precipitate was filtered off, and the resulting yellow solution was poured into saturated NaHCO3 solution and extracted with methylene chloride. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by vacuum distillation using a Kugelrohr apparatus to give 4g as a colorless liquid.
- Lee, Jae In
-
p. 125 - 128
(2017/06/07)
-
- Vitamin D3 analogues that contain modified A- and seco-B-rings as hedgehog pathway inhibitors
-
The hedgehog (Hh) signaling pathway is a developmental signaling pathway that has been implicated as a target for anti-cancer drug development in a variety of human malignancies. Several natural and synthetic vitamin D-based seco-steroids have been identified as potent inhibitors of Hh signaling with chemotherapeutic potential. These include the previously characterized analogue 4, which contains the northern CD-ring/side chain region of vitamin D3 (VD3) linked to an aromatic A-ring mimic through an ester bond. To further explore structure-activity relationships for this class of VD3-based Hh pathway inhibitors, we have designed, synthesized and evaluated several series of compounds that modify the length, composition, and stereochemical orientation of the ester linker. These studies have identified compounds 54 and 55, which contain an amine linker and an aromatic A-ring incorporating a para-phenol, as new lead compounds with enhanced potency against the Hh pathway (IC50 values Combining double low line 0.40 and 0.32 μM, respectively).
- Deberardinis, Albert M.,Raccuia, Daniel S.,Thompson, Evrett N.,Maschinot, Chad A.,Hadden, M. Kyle
-
p. 156 - 171
(2015/02/19)
-
- QUINAZOLINE DERIVATIVES AS TAM FAMILY KINASE INHIBITORS
-
Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders that are affected by the modulation of the activity of, e.g., the inhibition of, one or more members of the TAM family kinases.
- -
-
Paragraph 0180; 0181
(2015/06/08)
-
- Identification of two novel RET kinase inhibitors through MCR-based drug discovery: Design, synthesis and evaluation
-
From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.
- Frett, Brendan,Moccia, Marialuisa,Carlomagno, Francesca,Santoro, Massimo,Li, Hong-Yu
-
p. 714 - 723
(2015/01/16)
-
- HETEROCYCLIC INHIBITORS OF GLUTAMINASE
-
The invention relates to the heterocyclic compounds of Formula (I) as defined further herein, and pharmaceutical preparations thereof. The invention further relates to methods of treating cancer, immunological or neurological diseases using the heterocyclic compounds of the invention.
- -
-
Page/Page column 104
(2013/06/06)
-
- Synthesis of the tetracyclic core of berkelic acid using gold(I)-catalyzed hydroarylation and oxidative radical cyclizations
-
A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.
- Brimble, Margaret A.,Haym, Isabell,Sperry, Jonathan,Furkert, Daniel P.
-
supporting information
p. 5820 - 5823
(2013/02/23)
-
- Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4- tetrahydroisoquinoline derivatives as novel antihypertensive agents
-
A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3, 4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca2+ channel blockers.
- Watanuki, Susumu,Matsuura, Keisuke,Tomura, Yuichi,Okada, Minoru,Okazaki, Toshio,Ohta, Mitsuaki,Tsukamoto, Shin-Ichi
-
scheme or table
p. 1029 - 1037
(2011/10/18)
-
- 2-ARYL-PROPIONAMIDE DERIVATIVES USEFUL AS BRADYKININ RECEPTOR ANTAGONISTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
(R,S) 2-aryl-propionamide derivatives, or their single enantiomers (R) and (S) are disclosed useful in the treatment or prevention of symptoms and disorders such as pain and inflammation associated with the bradykinin B 1 pathway.
- -
-
Page/Page column 14
(2011/05/11)
-
- 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them
-
(R,S) 2-aryl-propionamide derivatives, or their single enantiomers (R) and (S) are disclosed useful in the treatment or prevention of symptoms and disorders such as pain and inflammation associated with the bradykinin B1 pathway.
- -
-
Page/Page column 7
(2011/05/08)
-
- Controlled anion migrations with a mixed metal Li/K-TMP amide: General application to benzylic metalations
-
A general method is described for benzylic metalation of o-, m-, and p-substituted toluenes using a mixed metal amide base generated from BuLi/KOtBu/TMP at -78 °C in THF. The excellent selectivity achieved can be rationalized by the ability of the mixed metal amide base to facilitate an anion migration from the kinetic (o-aryl) to the benzylic metalation site. Remarkably, this controlled anion migration is achievable with catalytic amounts of TMP at -78 °C.
- Fleming, Patricia,Oshea, Donal F.
-
supporting information; experimental part
p. 1698 - 1701
(2011/04/17)
-
- NOVEL ISOXAZOLE DRIVATIVE
-
Disclosed is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which has an agonistic activity on GPR120 and is therefore useful for the treatment of diabetes, obesity or hyperlipemia. [In formula (I), the A represents a phenyl group which may be substituted by a lower alkoxy group or the like; the 13 represents a bivalent group produced by removing two hydrogen atoms from a benzene ring which may be substituted by a halogen atom or the like; X represents a lower alkylene group having 2 to 4 carbon atoms in its main chain or the like, wherein a carbon atom constituting the main chain may be substituted by an oxygen atom or the like; and Y represents a hydrogen atom or the like.]
- -
-
Page/Page column 22
(2011/04/18)
-
- CARBOXYLIC ACID-CONTAINING COMPOUNDS, DERIVATIVES THEREOF, AND RELATED METHODS OF USE
-
Compounds that modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase) are described herein. Also disclosed are pharmaceutical compositions, methods of modulating the activity of gamma secretase, and methods of treating Alzheimer's Disease using the compounds described herein.
- -
-
Page/Page column 109
(2010/12/26)
-
- Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-inhibiting hypoxia-inducible factor
-
Aromatic analogues of the 2-oxoglutarate co-substrate of the hypoxia-inducible factor hydroxylases are shown to bind at the active site iron: Pyridine-2,4-dicarboxylate binds as anticipated with a single molecule chelating the iron in a bidentate manner. The binding mode of a hydroxamic acid analogue, at least in the crystalline state, is unusual because two molecules of the inhibitor are observed at the active site and partial displacement of the iron binding aspartyl residue was observed.
- Conejo-Garcia, Ana,McDonough, Michael A.,Loenarz, Christoph,McNeill, Luke A.,Hewitson, Kirsty S.,Ge, Wei,Liénard, Beno?t M.,Schofield, Christopher J.,Clifton, Ian J.
-
scheme or table
p. 6125 - 6128
(2010/12/19)
-
- The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages
-
The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
- Marino Jr., Joseph P.,Kallander, Lara S.,Ma, Chun,Oh, Hye-Ja,Lee, Dennis,Gaitanopoulos, Dimitri E.,Krawiec, John A.,Parks, Derek J.,Webb, Christine L.,Ziegler, Kelly,Jaye, Michael,Thompson, Scott K.
-
scheme or table
p. 5617 - 5621
(2010/04/30)
-
- SYNTHETIC LIGANDS SELECTIVE FOR LXRbeta OVER LXRalpha, IDENTIFICATION AND METHODS OF USE THEREOF
-
LXR nuclear receptor agonists have been previously shown to increase cholesterol efflux, raise plasma HDL cholesterol, stimulate cholesterol excretion, and reduce atherosclerotic lesions. However, these agonists have also been associated with the unwanted side effect of hypertriglyeridemia. This hypertriglyeridemia appears to be mediated by the LXRalpha subtype rather than LXRbeta, which suggests that LXRbeta-selective agonists are attractive candidates for modulation of human lipid metabolism. The present application provides novel LXRbeta-selective ligands that preferably modulate LXRbeta over LXRalpha. These ligands may be used to treat a variety of diseases associated with LXR, such as for example lipid metabolism disorders, atherosclerosis, Alzheimer disease, and inflammation.
- -
-
Page/Page column 7; Sheet 4/5
(2009/02/11)
-
- CYCLIC DIARYL ETHER COMPOUNDS AS ANTAGONISTS OF PROSTAGLANDIN D2 RECEPTORS
-
Described herein are compounds that are antagonists of PGD2 receptors. Also described are pharmaceutical compositions and medicaments that include the antagonists of PGD2 receptors described herein, as well as methods of using such antagonists of PGD2 receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.
- -
-
Page/Page column 102
(2009/10/09)
-
- AMINOALKYLPHENYL ANTAGONISTS OF PROSTAGLANDIN D2 RECEPTORS
-
Described herein are compounds that are antagonists of PGD2 receptors. Also described are pharmaceutical compositions and medicaments that include the compounds described herein that are antagonists of PGD2 receptors. Also described herein are methods of using such antagonists of PGD2 receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.
- -
-
Page/Page column 90
(2009/12/27)
-
- NOVEL PHENYL-ISOXAZOL-3-OL DERIVATIVE
-
The present invention relates to a compound represented by formula (I), which has a GPR120 agonist action and thus is useful for treatment of diabetes mellitus or hyperlipidemia, or a pharmaceutically acceptable salt thereof. In the formula, (AA) represents a phenyl or the like, which may be substituted with a lower alkoxy group or the like; (BB) represents a divalent group or the like, derived by removal of two hydrogen atoms from a benzene which may be substituted with a halogen atom or the like; X represents a spacer having a main chain composed of 1-8 carbon atoms wherein 1-3 carbon atoms in the main chain may be substituted with an oxygen atom or the like; and Y represents a hydrogen atom or the like.
- -
-
Page/Page column 40
(2009/09/26)
-
- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
-
The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
- -
-
Page/Page column 30
(2008/06/13)
-
- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
-
The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
- -
-
Page/Page column 26
(2010/11/27)
-
- ALKYLAMINE-SUBSTITUTED BICYCLIC ARYL COMPOUNDS USEFUL AS MODULATORS OF PPAR
-
The present invention relates to novel alkylamine-substituted bicyclic aryl compounds, pharmaceutical compositions comprising the same, useful as modulators of PPAR, and methods for the treatment or prevention of disease.
- -
-
Page/Page column 12; 21-22
(2008/06/13)
-
- 3,4,5-Trisubstituted isoxazoles as novel PPARδ agonists. Part 2
-
A series of PPARδ-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARδ agonist with good in vivo PK properties in mouse (Cmax = 5.1 μM, t1/2 = 3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARδ is discussed.
- Epple, Robert,Azimioara, Mihai,Russo, Ross,Xie, Yongping,Wang, Xing,Cow, Christopher,Wityak, John,Karanewsky, Don,Bursulaya, Badry,Kreusch, Andreas,Tuntland, Tove,Gerken, Andrea,Iskandar, Maya,Saez, Enrique,Martin Seidel,Tian, Shin-Shay
-
p. 5488 - 5492
(2007/10/03)
-
- Diversity synthesis using the complimentary reactivity of rhodium(II)- and palladium(II)-catalyzed reactions
-
Rhodium(II)-catalyzed reactions of aryldiazoacetates can be conducted in the presence of iodide, triflate, organoboron, and organostannane functionality, resulting in the formation of a variety of cyclopropanes or C-H insertion products with high stereoselectivity. The combination of the rhodium(II)-catalyzed reaction with a subsequent palladium(II)-catalyzed Suzuki coupling offers a novel strategy for diversity synthesis.
- Ni, Aiwu,France, Jessica E.,Davies, Huw M. L.
-
p. 5594 - 5598
(2007/10/03)
-
- NIACIN RECEPTOR AGONISTS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
-
The present invention encompasses compounds of Formula (I); as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating dyslipidemias. Pharmaceutical compositions and methods of use are also included.
- -
-
Page/Page column 34-35
(2010/11/08)
-
- BICYCLIC DERIVATIVES AS PPAR MODULATORS
-
The present invention is directed to compounds represented by the following structural formula, Formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: (a) R2 is selected from the group consisting of C0-C8 alkyl and C1-4- heteroalkyl; (b) X is selected from the group consisting of a single bond, O, S, S(O)2 and N; (c) U is an aliphatic linker wherein one carbon atom of the aliphatic linker is optionally replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with from one to four substituents each independently selected from R30; (d) Y is selected from the group consisting of C, O, S, NH and a single bond; and (e) E is C(R3)(R4)A or A.
- -
-
Page/Page column 51
(2008/06/13)
-
- AZAINDOLES USEFUL AS INHIBITORS OF ROCK AND OTHER PROTEIN KINASES
-
The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
- -
-
Page/Page column 168
(2008/06/13)
-
- COMPOSITIONS USEFUL AS INHIBITORS OF ROCK AND OTHER PROTEIN KINASES
-
The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
- -
-
Page/Page column 72
(2008/06/13)
-
- (5- (2-PHENYL)-THIAZOL-5-YLMETHOXY)-INDOL-1-YL) -ACETIC ACID DERIVATIVES AND RELATED COMPOUNDS AS MODULATORS OF THE HUMAN PPAR-DELTA RECEPTOR FOR THE TREATMENT OF METABOLIC DISORDERS SUCH AS TYPE 2 DIABETES
-
Disclosed are compounds having the structure of Formula (I) and pharmaceutically acceptable salts and solvates thereof [A]-[B]-[C] (I) wherein (a) [A] is [H]-[L]; wherein [H] represents a CCOH (or a hydrolyzable ester thereof) or tetrazole group [L] is: formula (II), b) [B] is a ring system selected from the group consisting of: e.g. formula (III); (IIIA), c) [C] is e.g. formula (IV); the other substituents and variables are defined in the claims; as modulators of the human PPAR-delta receptor for the treatment of metabolic disorders such as type 2 diabetes.
- -
-
Page/Page column 144-145
(2008/06/13)
-
- 3,4-DISUBSTITUTED MALEIMIDES FOR USE AS VASCULAR DAMAGING AGENTS
-
This invention relates to novel compounds of Formula (I) for use as vascular damaging agents: Formula (I) wherein Rl, R7, R8, R9, ARI, AR2, AR3, p, q and r are as described in the specification. The invention also relates to methods for preparing compounds of Formula (I), to their use as medicaments (including methods for the treatment of angiogenesis or disease states associated with angiogenesis) and to pharmaceutical compositions containing compounds of Formula (I).
- -
-
Page/Page column 40
(2008/06/13)
-
- 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors
-
The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCLS-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
- Allegretti, Marcello,Bertini, Riccardo,Cesta, Maria Candida,Bizzarri, Cinzia,Di Bitondo, Rosa,Di Cioccio, Vito,Galliera, Emanuela,Berdini, Valerio,Topai, Alessandra,Zampella, Giuseppe,Russo, Vincenzo,Di Bello, Nicoletta,Nano, Giuseppe,Nicolini, Luca,Locati, Massimo,Fantucci, Piercarlo,Florio, Saverio,Colotta, Francesco
-
p. 4312 - 4331
(2007/10/03)
-
- IMINO ETHER DERIVATIVE COMPOUNDS AND DRUGS CONTAINING THE COMPOUNDS AS THE ACTIVE INGREDIENT
-
The compound represented by formula (I) (wherein R1 and R2 are cyclic group which may have a substituent(s) and so on.; W is a spacer of which main chain has an atom number of 1-6.; X is -O- and so on.; ringA is cyclic group which may have a substituent(s).; Y is a spacer of which main chain has an atom number of 1-6 and so on.; Z is acidic group.) a salt thereof, a solvent thereof or an N-oxide thereof or a prodrug thereof Since the compounds in the present invention have a regulatory activity for peroxisome proliferator activated receptor, the compounds in the present invention are useful as a preventive and/or therapeutic agent for diseases associating metabolic disorders (e.g., hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipidemia, atherosclerosis, hypertension, circulatory diseases, overeating, ischemic heart diseases, etc., an HDL cholesterol-elevating agent, an LDL cholesterol and/or a VLDL cholesterol-lowering agent and a drug for relief from risk factors of diabetes or metabolic syndrom.
- -
-
Page/Page column 22-23
(2010/02/14)
-
- Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics
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The present invention relates to pyridoindolone derivatives substituted in the 3-position by a phenyl of general formula (I): to processes for preparing the same and to their use in therapeutics.
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Page/Page column 11
(2010/02/15)
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- FUSED HETEROCYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: wherein (a) X is selected from the group consisting of a single bond, O, S. S(O)2 and N; (b) U is an aliphatic linker; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; (d) E is C(R3) (R4)A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamidek, sulfonamide and acylsulfonamide; (e) B is selected from the group consisting of S, O, C, and N; (f) Z is selected from the group consisting of N and C; with the proviso that when B is C then Z is N.
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- COMPOSITIONS USEFUL AS INHIBITORS OF ROCK AND OTHER PROTEIN KINASES
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The present invention relates to substitute thiazole and thiophene derivatives useful as inhibitors of rock and other protein kinaeses. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders, including proliferative, cardiac and neurodegenerative diseases.
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Page 113-114
(2010/02/07)
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- AMIDE COMPOUNDS AND METHODS OF USING THE SAME
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Disclosed is a compound having the formula (I) pharmaceutically acceptable salts or solvates thereof and pharmaceutical compositions containing the same, wherein the structural variables are as defined herein. The compounds, salts and solvates of this invention are useful as LXR agonists.
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- GFAT INHIBITORS
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Compounds of formula (I) are provided as well as pharmaceutically acceptable salts and esters thereof, wherein the substituents are as disclosed in the specification. The compounds have utility for the treatment of type 2 diabetes mellitus.
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- THIOPHENE DERIVATIVE PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: (a) X is selected from the group consisting of O, S, S(O)2, N, and a bond; (b) U is an aliphatic linker wherein one carbon atom of the aliphatic linker may be replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with R30; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; and (d) E is C(R3)(R4)A or A.
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- PHARMACEUTICALLY ACTIVE BENZOXAZOLE, BENZTHIAZOLE AND BENZIMIDAZOLE ACID DERIVATIVES
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Compounds of formula (I): wherein R1, R2 and R3 are independently, hydrogen, halogen, CF3, OR6, NR7R8, NR8COR10, NR8SO2R10 or C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy or NR7R8; R4 is NR8CONR8R9, NR8COR9, NR8SO2R9, or W-CONR8R9, where W is a bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; and R5 is Formula (A) methods for their synthesis, pharmaceutical compositions comprising them and their use in medicine, in particular for the treatment of cancer.
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- ACID AND ESTER COMPOUNDS AND METHODS OF USING THE SAME
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Disclosed is a compound of having the formula (II-A), pharmaceutically acceptable salts or solvates thereof and pharmaceutical compositions containing the same, wherein the structural variables are as defined herein. The compounds, salts and solvates of this invention are useful as LXR agonists.
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Page/Page column 41
(2008/06/13)
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- Isoquinoline derivatives
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Disclosed are isoquinolino derivatives of the formula wherein Y is >C═O or —CH2—, Z is >C═O or —CH2—, and R1, R2 and m are as defined herein as well as the pharmaceutically acceptable salts thereof. These compounds are MAO-B selective inhibitors useful, inter alia, in the treatment of Alzheimer's disease and/or senile dementia.
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- One-pot synthesis of 6-hydroxyisochromans: The example of demethyl-oxa-coclaurine
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Using a modified oxa-Pictet Spengler reaction that we recently described, we synthesized 6-hydroxy-isochromans and their 7-hydroxy derivatives. The successful one step synthesis did not require protecting groups and provided high yields. The obtainment of 1-(4′ -hydroxybenzyl)-6,7-dihydroxyisochroman (1) indicates that this protocol can be used to synthesize oxygenated analogues of benzyl-tetrahydroisoquinoline alkaloids, such as demethyl-coclaurine (2). This methodology could provide a general procedure for the synthesis of hydroxyisochromans. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Guiso, Marcella,Bianco, Armandodoriano,Marra, Carolina,Cavarischia, Claudia
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p. 3407 - 3411
(2007/10/03)
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