- Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma
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Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.
- Perry, Matthew W. D.,Bj?rhall, Karin,Bold, Peter,Br?lls, Mikael,B?rjesson, Ulf,Carlsson, Johan,Chang, Hui-Fang Amy,Chen, Yunhua,Eriksson, Anders,Fihn, Britt-Marie,Fransson, Rebecca,Fredlund, Linda,Ge, Hongbin,Huang, Haijuan,Karabelas, Kostas,Lamm Bergstr?m, Eva,Lever, Sarah,Lindmark, Helena,Mogemark, Mickael,Nikitidis, Antonios,Palmgren, Anna-Pia,Pemberton, Nils,Petersen, Jens,Rodrigo Blomqvist, Mio,Smith, Reed W.,Thomas, Matthew J.,Ullah, Victoria,Tyrchan, Christian,Wennberg, Tiiu,Westin Eriksson, Annika,Yang, Wenzhen,Zhao, Shuchun,?ster, Linda
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Read Online
- Enhancing performance for blue TADF emitters by introducing intramolecular CH?N hydrogen bonding between donor and acceptor
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Three novel thermally activated delayed fluorescence (TADF) emitters, named MCZ-B-DTM, MCZ-P2-DTM and MCZ-P3-DTM are designed and synthesized for fabricating blue emission devices. The position of nitrogen atom in pyridine ring is varied relative to the donor unit and the presence of CH?N hydrogen bonding in MCZ-P3-DTM is confirmed by theoretic simulation and 1H NMR analysis. Due to the introduction of CH?N hydrogen bonding between donor and acceptor, the dihedral angles, photophysical properties, together with thermal stabilities, of the targeted compounds are regulated ingeniously. As a consequence, MCZ-P3-DTM displays an increase of the molar extinction coefficient obviously and offers a higher PLQY of 60.1%. The TADF device adopting MCZ-P3-DTM as emitter shows a maximum external quantum efficiency (EQE) of 12.1%, which is superior to those of MCZ-B-DTM and MCZ-P2-DTM, demonstrating the introducing of intramolecular hydrogen bonding interactions between donor and acceptor is an efficient strategy for future structural design of TADF emitters.
- Ma, Fulong,Cheng, Yu,Zhang, Xiuxuan,Gu, Xiaofei,Zheng, Yu,Hasrat, Kamvan,Qi, Zhengjian
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Read Online
- Structure-based design and profiling of novel 17β-HSD14 inhibitors
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The human enzyme 17β-hydroxysteroid dehydrogenase 14 (17β-HSD14) oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. However, the physiological role of the enzyme remains unclear. We recently des
- Braun, Florian,Bertoletti, Nicole,M?ller, Gabriele,Adamski, Jerzy,Frotscher, Martin,Guragossian, Nathalie,Madeira Gírio, Patrícia Alexandra,Le Borgne, Marc,Ettouati, Laurent,Falson, Pierre,Müller, Sebastian,Vollmer, Günther,Heine, Andreas,Klebe, Gerhard,Marchais-Oberwinkler, Sandrine
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Read Online
- Phenylpyridine compound and preparation and application thereof
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The invention discloses a phenylpyridine compound and preparation and application thereof. The compound is used as a tumor multidrug resistance reversal agent and a chemotherapeutic drug sensitizer. Pharmacological experiment results show that the compound provided by the invention has excellent tumor multidrug resistance reversal activity and sensitization chemotherapy drug activity, and can be clinically used as a malignant tumor multidrug resistance reversal agent and a chemotherapy drug sensitizer.
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Paragraph 0062-0064
(2021/03/13)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Heterocyclic compounds as Wee1 inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0457-0459
(2019/04/25)
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- Pyridine-amide-oxazoline ligand, synthesizing method, metal complex and application thereof
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The invention discloses a pyridine-amide-oxazoline ligand. The ligand is a compound as shown in a formula (I) or antimer or despinner of the compound as shown in the formula (I), wherein R1 and R2 arerespectively one of hydrocarbyl, benzyl, phenyl or subs
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Paragraph 0042-0046
(2019/04/27)
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- QUINOLINE DERIVATIVES USEFUL AS TYROSINE KINASE INHIBITORS
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Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure (I) and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, X, Y1, Y2, Y3 and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.
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Paragraph 0207
(2019/12/25)
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- ANTIBACTERIAL THERAPEUTICS AND PROPHYLACTICS
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The present disclosure relates generally to novel molecules, compositions, and formulations for treatment of bacterial infections in general and more specifically to bacterial infections with antibiotic resistant pathogens.
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Paragraph 00328; 00366
(2017/02/24)
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- Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors
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FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50–100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.
- Liu, Yang,Peng, Xia,Guan, Xiaocong,Lu, Dong,Xi, Yong,Jin, Shiyu,Chen, Hui,Zeng, Limin,Ai, Jing,Geng, Meiyu,Hu, Youhong
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p. 122 - 132
(2016/10/25)
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- PYRIMIDINE AND TRIAZINE DERIVATIVES AND THEIR USE AS AXL INHIBITORS
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Compounds of the general formula(I): (I) processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Page/Page column 53
(2016/07/05)
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- Rhodium(III)-catalyzed oxidative olefination of picolinamides: Convenient synthesis of 3-alkenylpicolinamides
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A rhodium(III)-catalyzed selective olefination of picolinamide derivatives has been developed. The reaction shows high regioselectivity, low catalyst loading (0.5 mol%), high yield and good functional group tolerance, providing a convenient strategy for the synthesis of 3-alkenylpicolinamides.
- Zhou, Jun,Li, Bo,Qian, Zhen-Chao,Shi, Bing-Feng
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supporting information
p. 1038 - 1046
(2014/04/03)
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- CXCR4 Receptor Antagonists
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Disclosed are compounds that are antagonists of the CXCR4 receptor.
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Paragraph 0237
(2013/11/06)
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- NOVEL MICROBIOCIDES
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The present invention provides compounds of formula (I) wherein A1, A2, R1, D1, D2, Y3 and X are as defined in the claims. The invention further relates to compositions which comprise these
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Page/Page column 113-114
(2012/05/31)
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- Ruthenium(II) pincer complexes with oxazoline arms for efficient transfer hydrogenation reactions
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Well-defined PNNCN pincer ruthenium complexes bearing both strong phosphine and weak oxazoline donors were developed. These easily accessible complexes exhibit significantly better catalytic activity in transfer hydrogenation of ketones compared to their PN3P analogs. These reactions proceed under mild and base-free conditions via protonation- deprotonation of the 'NH' group in the aromatization-dearomatization process.
- Chen, Tao,He, Li-Peng,Gong, Dirong,Yang, Limin,Miao, Xiaohe,Eppinger, J?rg,Huang, Kuo-Wei
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supporting information; experimental part
p. 4409 - 4412
(2012/09/25)
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- NOVEL MICROBIOCIDAL OXIME ETHERS
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The present invention provides compounds of formula (I) wherein D1, D2, D3, G1, G2, G3, Y3, Y4, Y6, p and X are as defined in the claims. The invention furt
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Page/Page column 108
(2012/09/21)
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- Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): Potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts
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The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.
- Boulahjar, Rajaa,Ouach, Aziz,Matteo, Chiurato,Bourg, Stephane,Ravache, Myriam,Guével, Rémy Le,Marionneau, Séverine,Oullier, Thibauld,Lozach, Olivier,Meijer, Laurent,Guguen-Guillouzo, Christiane,Lazar, Sa?d,Akssira, Mohamed,Troin, Yves,Guillaumet, Gérald,Routier, Sylvain
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p. 9589 - 9606
(2013/01/16)
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- Efficient enhancement of copper-pyridineoxazoline catalysts through immobilization and process design
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Copper-pyridineoxazoline (Cu-pyox) complexes are poor homogeneous catalysts for asymmetric cyclopropanation reactions. Pyox ligands have been immobilized by polymerization of monomers possessing a vinyl group directly attached to position 6 with styrene a
- Aranda,Cornejo,Fraile,Garcia-Verdugo,Gil,Luis,Mayoral,Martinez-Merino,Ochoa
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supporting information; experimental part
p. 983 - 990
(2011/06/19)
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- BENZOTHIAZOLE AND BENZOOXAZOLE DERIVATIVES AND METHODS OF USE
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Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions of compounds of formula (I), methods for using such compounds and compositions, and a process for preparing the compounds.
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Page/Page column 57
(2009/07/10)
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- Pyridine amides as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1
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Several series of pyridine amides were identified as selective and potent 11β-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH2SO2, CH2S, CH2/su
- Wang, Haixia,Ruan, Zheming,Li, James J.,Simpkins, Ligaya M.,Smirk, Rebecca A.,Wu, Shung C.,Hutchins, Robert D.,Nirschl, David S.,Van Kirk, Katy,Cooper, Christopher B.,Sutton, James C.,Ma, Zhengping,Golla, Rajasree,Seethala, Ramakrishna,Salyan, Mary Ellen K.,Nayeem, Akbar,Krystek Jr., Stanley R.,Sheriff, Steven,Camac, Daniel M.,Morin, Paul E.,Carpenter, Brian,Robl, Jeffrey A.,Zahler, Robert,Gordon, David A.,Hamann, Lawrence G.
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body text
p. 3168 - 3172
(2009/04/11)
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- Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
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Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure: or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein G, L, Q, Z, R6, R7, and R8 are defined herein.
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Page/Page column 32
(2010/11/24)
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- BENZOFURAN DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS
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The invention relates to novel heterocycles of formula (I), processes for their preparation and their use for preparing medicaments for the treatment or prophylaxis of disorders, especially of hyperproliferative disorders.
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Page/Page column 91
(2008/06/13)
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- NITROGEN-CONTAINING HETEROCYCLE DERIVATIVE AND ORGANIC ELECTROLUMINESCENT ELEMENT USING THE SAME
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A novel derivative of heterocyclic compound having nitrogen atom with a structure made by bonding special groups to benzimidazole, a material for an organic electroluminescence (EL) device comprising the derivative of heterocyclic compound having nitrogen atom and an organic electroluminescence device comprising at least one organic compound layer containing a light emitting layer sandwiched between a pair of electrodes, wherein the device contains the derivative of heterocyclic compound having nitrogen atom. An organic EL device achieving elevation of luminance and of efficiency in light emission even under low driving voltage is obtainable by an employment of the derivative of heterocyclic compound having nitrogen atom for at least one layer composing organic compound layers of the EL device.
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Page/Page column 36
(2010/02/14)
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- Preparation and palladium-catalysed arylation of indolylzinc halides
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Indolylzinc halides are prepared by two methods: transmetallation of indolyllithiums with zinc chloride and oxidative addition of active zinc to iodoindoles. The palladium-catalysed reaction of the indolylzinc halides provides a practical method for synthesizing arylindoles.
- Sakamoto, Takao,Kondo, Yoshinori,Takazawa, Nobuo,Yamanaka, Hiroshi
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p. 1927 - 1934
(2007/10/03)
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- Leukotriene-B4 derivatives, process for their production and their use as pharmaceutical agents
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The present invention relates to a leukotriene-B4 analog according to formula I STR1 in which R1 is a COOR2 group, wherein R2 is a C2-4 -alkyl group; B is a C1-3 -alkylene group, a radical
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- Substituent Effects in Non-Aromatic Nitrogen Heterocycles: Alkaline Hydrolysis of Methyl N-Methyl(oxo)dihydropyridinecarboxylates and Diaza Analogues
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Ester hydrolysis studies on some isomeric methoxycarbonyl derivatives of N-methylpyridin-2- and 4-ones show that reaction rates are affected by the relative positions of CO2Me, =O and NMe functions in ways which could not be predicted.However, from limited results for analogous pyrimidine derivatives, it seems that reactivity in these polyfunctional compounds can be predicted from the pyridine data by assuming additivity of effects.
- Deady, Leslie W.
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p. 637 - 641
(2007/10/02)
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