- Developing dual functional allosteric modulators of GABAA receptors
-
Positive modulators at benzodiazepine sites of α2- and α3-containing GABAA receptors are believed to be anxiolytic. Negative allosteric modulators of α5-containing GABAA receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure-activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at α2-/α3-containing GABAA receptors and negative modulators at α5-containing GABAA receptors. In addition, these compounds showed no functional activity at α1-containing GABAA receptors. Such dual functional modulators of GABAA receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses.
- Liu, Xiaodong F.,Chang, Hui-Fang,Schmiesing, Richard Jon,Wesolowski, Steven S.,Knappenberger, Katharine S.,Arriza, Jeffrey L.,Chapdelaine, Marc J.
-
-
Read Online
- New vasorelaxant indole alkaloids, taberniacins A and B, from Tabernaemontana divaricata
-
Taberniacins A (1) and B (2), new indole alkaloids, were isolated from the stems of Tabernaemontana divaricata (Apocynaceae). Structure elucidation of 1 and 2 was based on spectroscopic methods and total synthesis. Each alkaloid showed vasorelaxant activity against phenylephrine-induced contraction of isolated rat aorta.
- Hirasawa, Yusuke,Dai, Xin,Deguchi, Jun,Hatano, Shota,Sasaki, Tadahiro,Ohtsuka, Ruri,Nugroho, Alfarius Eko,Kaneda, Toshio,Morita, Hiroshi
-
-
Read Online
- From ergolines to indoles: Improved inhibitors of the human H3 receptor for the treatment of narcolepsy
-
Ergolines were recently identified as a novel class of H3 receptor (H3R) inverse agonists. Although their optimization led to drug candidates with encouraging properties for the treatment of narcolepsy, brain penetration remained low. To overcome this issue, ergoline 1 ((6aR,9R,10aR)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide)) was transformed into a series of indole derivatives with high H3R affinity. These new molecules were profiled by simultaneous determination of their brain receptor occupancy (RO) levels and pharmacodynamic (PD) effects in mice. These efforts culminated in the discovery of 15m ((R)-1-isopropyl-5-(1-(2-(2-methylpyrrolidin-1-yl)ethyl)-1H-indol-4-yl)pyridin-2(1H)-one), which has an ideal profile showing a strong correlation of PD effects with RO, and no measurable safety liabilities. Its desirably short duration of action was confirmed by electroencephalography (EEG) measurements in rats.
- Auberson, Yves P.,Troxler, Thomas,Zhang, Xuechun,Yang, Charles R.,Feuerbach, Dominik,Liu, Yu-Chih,Lagu, Bharat,Perrone, Mark,Lei, Lijun,Shen, Xiaoxia,Zhang, Dushan,Wang, Chunxiu,Wang, Tie-Lin,Briner, Karin,Bock, Mark G.
-
-
Read Online
- A predictive model for additions to: N -alkyl pyridiniums
-
Disclosed in this communication is a thorough study on the dearomative addition of organomagnesium nucleophiles to N-alkyl pyridinium electrophiles. The regiochemical outcomes have observable and predictable trends associated with the substituent patterns on the pyridinium electrophile. Often, the substituent effects can be either additive, giving high selectivities, or ablative, giving competing outcomes. Additionally, the nature of the organometallic nucleophilic component was also investigated for its role in the regioselective outcome. The effects of either reactive component are important to both the overall reactivity and site of nucleophilic addition. The utility of these observed trends is demonstrated in a concise, dearomative synthesis of a tricyclic compound shown to have insecticidal activity. This journal is
- Knight, Brian J.,Tolchin, Zachary A.,Smith, Joel M.
-
supporting information
p. 2693 - 2696
(2021/03/18)
-
- Phenylpyridine compound and preparation and application thereof
-
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.
- -
-
Paragraph 0074-0076
(2021/03/13)
-
- Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain
-
Pharmacological targeting of tumor associated macrophages and microglia in the tumor microenvironment is a novel therapeutic strategy in the treatment of glioblastoma multiforme. As such, the colony stimulating factor-1 receptor (CSF-1R) has been identified as a druggable target. However, no validated companion diagnostic marker for these therapies exists to date. Towards development of a CSF-1R PET tracer, a set of six compounds based on recently reported CSF-1R inhibitor 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide (Compound 5) was designed, synthesized and evaluated in vitro for potency and selectivity. The highest affinity for CSF-1R was found for compound 5 (IC50: 2.7 nM). Subsequent radiosynthesis of [11C]5 was achieved in 2.0 ± 0.2% yield (decay corrected to start of synthesis) by carbon-11 carbon monoxide aminocarbonylation in 40 min after end of bombardment. In vitro autoradiography with [11C]5 on rat brain sections demonstrated high specific binding, but also strong off-target binding. Ex vivo, only intact tracer was observed in blood plasma at 90 min post injection in healthy rats. PET scanning results demonstrated negligible brain uptake under baseline conditions and this brain uptake did not increase by blocking of efflux transporters using Tariquidar. To conclude, [11C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [11C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain.
- Chin, Frederick T.,Kooijman, Esther J. M.,Nezam, Madina,Reyes, Samantha T.,Shen, Bin,Windhorst, Albert D.,van der Wildt, Berend
-
-
- 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)
-
- Design, synthesis, and biological evaluation of novel Bcr-AblT315I inhibitors incorporating amino acids as flexible linker
-
Despite the success of imatinib in CML therapy through Bcr-Abl inhibition, acquired drug resistance occurs over time in patients. In particular, the resistance caused by T315I mutation remains a challenge in clinic. Herein, we embarked on a structural optimization campaign aiming at discovery of novel Bcr-Abl inhibitors toward T315I mutant based on previously reported dibenzoylpiperazin derivatives. We proposed that incorporation of flexible linker could achieve potent inhibition of Bcr-AblT315I by avoiding steric clash with bulky sidechain of Ile315. A library of 28 compounds with amino acids as linker has been developed and evaluated. Among them, compound AA2 displayed the most potent activity against Bcr-AblWT and Bcr-AblT315I, as well as toward Bcr-Abl driven K562 and K562R cells. Further investigations indicated that AA2 could induce apoptosis of K562 cells and down regulate phosphorylation of Bcr-Abl. In summary, the compounds with amino acid as novel flexible linker exhibited certain antitumor activities, providing valuable hints for the discovery of novel Bcr-Abl inhibitors to overcome T315I mutant resistance, and AA2 could be considered as a candidate for further optimization.
- Li, Yanchen,Li, Zilong,Liu, Nanxin,Pan, Xiaoyan,Shan, YuanYuan,Wang, Kai,Zhang, Jie,Zhang, Qingqing
-
-
- Enhancing performance for blue TADF emitters by introducing intramolecular CH?N hydrogen bonding between donor and acceptor
-
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
-
p. 245 - 253
(2019/03/27)
-
- Chemical conversion of nicotinamide into type I positive allosteric modulator of α7 nAChRs
-
Structural modifications of nicotinamide, a form of vitamin B3, gave rise to a series of compounds (8aa–8ce) that exhibit activities as type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus oocytes in two-electrode voltage clamp assay. The compound 8ai was a potent and efficacious PAM with an EC50 = 3.34 ± 1.13 μM and the maximum activation effect of α7 current over 1474 ± 246% in the presence of acetylcholine (100 μM). It is highly specific to α7 nAChR over other subtypes of nAChR and 5-HT3A receptors. The structure–activity relationship analysis identified a key skeleton of nicotinamide nucleus critical for biological activity. Taken together, the 8ai as a type I PAM of α7 nAChR may be beneficial for improvement of cognitive deficit.
- Li, Xin,Xie, Wenjun,Wang, Xintong,Huang, Zongze,Bian, Xiling,Wang, KeWei,Sun, Qi
-
supporting information
p. 1928 - 1933
(2019/06/04)
-
- Hydroxyproline peptoid derivative and preparation method and application thereof
-
Disclosed are a hydroxyproline peptoid derivative and a preparation method and application thereof. With biphenyl pyridine as a hinge region binding fragment, by adopting a design strategy of a fragment drug and introducing L-hydroxyproline as a flexible Linker, a peptoid micromolecule-like compound library with kinase inhibition activity is constructed, and through screening of ADP-Glo and otheractivity tests, a peptoid tyrosine-like kinase inhibitor which has Bcr-Abl kinase inhibition activity and prevents the proliferation of tumor cells is found. The compound can be used for preparing anti-tumor drugs and has the activity of inhibiting Bcr-Abl and Bcr-AblT315I kinases and activity of inhibiting the cell proliferation of K562 cells. By introducing the L-hydroxyproline, the structural diversity of the Bcr-Abl inhibitor is expanded, the activity result shows that the introduction of proline has a certain effect on the inhibition activity of the compound, and the proline can serve asa novel pharmacological-effect fragment of the Bcr-Abl tyrosine kinase inhibitor.
- -
-
Paragraph 0063-0065
(2019/06/27)
-
- A containing tert-Leu [...] compound and its preparation method and application (by machine translation)
-
A containing tert-Leu [...] compound and its preparation method and application, the use of acylated, Suzuki coupling, condensation of the reaction to synthesize the target compound, and construct the compound library, the compound has the molecular structure of the Bcr - Abl small molecule tyrosine kinase inhibitor, this invention adopts the fragment-based drug design strategy, to biphenyl pyridine is hinge-binding fragment, is introduced into the L - tert-leucine is a flexible Linker, to construct a kinase-inhibiting activity of a small molecule compound library [...], and through the ADP - Glo screening it has been found that the kinase activity of Bcr - Abl kinase-inhibiting activity of a tyrosine kinase inhibitor. Kinase screening test indicates that this compound to the Abl kinase, T315I mutation Abl kinase has a certain inhibition activity, cell proliferation experiment shows that most of the compound to the K562 cells with certain inhibiting activity. (by machine translation)
- -
-
Paragraph 0055-0057
(2019/07/04)
-
- Hemozoin inhibiting 2-phenylbenzimidazoles active against malaria parasites
-
The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1H-benzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124. Further narrowing to compounds with terminal aryl ring substituents only, reduced the library to 18, 83% of which were found to inhibit β-hematin formation 100 μM and 50% parasite growth 2 μM. Four compounds showed nanomolar parasite growth inhibition activities, no cross-resistance in a chloroquine resistant strain and low cytotoxicity. QSAR analysis showed a strong association of parasite growth inhibition with inhibition of β-hematin formation and the most active compound inhibited hemozoin formation in P. falciparum, with consequent increasing exchangeable heme. Pioneering use of molecular docking for this system demonstrated predictive ability and could rationalize observed structure activity trends.
- L'abbate, Fabrizio P.,Müller, Ronel,Openshaw, Roxanne,Combrinck, Jill M.,de Villiers, Katherine A.,Hunter, Roger,Egan, Timothy J.
-
p. 243 - 254
(2018/10/15)
-
- Triazolo-pyridazine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient
-
The present invention relates to a triazolopyridazine derivative, a production method thereof, and a pharmaceutical composition for preventing or treating diseases associated with activation of Brutonandprime;s tyrosine kinase (BTK) containing the same as an active ingredient. According to the present invention, the triazolopyridazine derivative excellently inhibits BTK, and thus can be useful for preventing or treating diseases associated with activation of BTK, especially cancer or autoimmune diseases.COPYRIGHT KIPO 2018
- -
-
Paragraph 0396-0399
(2018/10/16)
-
- Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1
-
Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.
- Schoepfer, Joseph,Jahnke, Wolfgang,Berellini, Giuliano,Buonamici, Silvia,Cotesta, Simona,Cowan-Jacob, Sandra W.,Dodd, Stephanie,Drueckes, Peter,Fabbro, Doriano,Gabriel, Tobias,Groell, Jean-Marc,Grotzfeld, Robert M.,Hassan, A. Quamrul,Henry, Chrystèle,Iyer, Varsha,Jones, Darryl,Lombardo, Franco,Loo, Alice,Manley, Paul W.,Pellé, Xavier,Rummel, Gabriele,Salem, Bahaa,Warmuth, Markus,Wylie, Andrew A.,Zoller, Thomas,Marzinzik, Andreas L.,Furet, Pascal
-
supporting information
p. 8120 - 8135
(2018/09/18)
-
- Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors
-
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
-
p. 122 - 132
(2016/10/25)
-
- Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
-
Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 ? resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.
- Schwertz, Geoffrey,Witschel, Matthias C.,Rottmann, Matthias,Bonnert, Roger,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Jaruwat, Aritsara,Ittarat, Wanwipa,Sch?fer, Anja,Aponte, Raphael A.,Charman, Susan A.,White, Karen L.,Kundu, Abhijit,Sadhukhan, Surajit,Lloyd, Mel,Freiberg, Gail M.,Srikumaran, Myron,Siggel, Marc,Zwyssig, Adrian,Chaiyen, Pimchai,Diederich, Fran?ois
-
supporting information
p. 4840 - 4860
(2017/06/28)
-
- INDAZOLE INHIBITORS OF THE WNT SIGNAL PATHWAY AND THERAPEUTIC USES THEREOF
-
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases due to mutations in Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
- -
-
Paragraph 0091; 0092
(2015/11/16)
-
- Discovery of novel Bcr-Abl inhibitors with diacylated piperazine as the flexible linker
-
Forty-two compounds (series 8, 9 and 10) incorporated with diacylated piperazine have been synthesized and evaluated as novel Bcr-Abl inhibitors based on 'six-atom linker'. Five of them, 8d, 8h, 8l, 10m and 10p, displayed potent Bcr-Abl inhibitory activity comparable with Imatinib. Moreover, compounds 8e, 10q, 10s, and 10u were potent Bcr-Abl inhibitors with IC50 values at the sub-micromolecular level. Most compounds exhibited moderate to high antiproliferative activity against K562 cells. In particular, compound 9e was the most promising Bcr-Abl inhibitor. Docking studies revealed that the binding modes of these compounds were similar with Imatinib. These compounds could be considered as promising lead compounds for further optimization.
- Pan, Xiaoyan,Dong, Jinyun,Shi, Yaling,Shao, Ruili,Wei, Fen,Wang, Jinfeng,Zhang, Jie
-
p. 7050 - 7066
(2015/06/25)
-
- Discovery of 7-aryl-substituted (1,5-naphthyridin-4-yl)ureas as Aurora kinase inhibitors
-
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents. Promising Aurora inhibitors: Herein we report a series of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of nanomolar-range Aurora kinase inhibitors. The described derivatives have good cell-penetration parameters and safety profiles, but their efficiency toward signaling pathways are insufficient to induce cell death. We also highlight their selectivity toward a panel of seven cancer-related protein kinases. Copyright
- Defaux, Julien,Antoine, Maud,Le Borgne, Marc,Schuster, Tilmann,Seipelt, Irene,Aicher, Babette,Teifel, Michael,Guenther, Eckhard,Gerlach, Matthias,Marchand, Pascal
-
p. 217 - 232
(2014/01/17)
-
- HETEROCYCLIC-SUBSTITUTED BENZOFURAN DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
-
The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
- -
-
Paragraph 45-46
(2013/03/26)
-
- HETEROCYCLIC-SUBSTITUED BENZOFURAN DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
-
The present invention relates to compounds of formula (1) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
- -
-
Paragraph 55-56
(2013/03/26)
-
- COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE ACTIVITY OF ABL1, ABL2 AND BCR-ABL1
-
The present invention relates to compounds of formula I: in which Y, Y1, Y 4, Y5, Y 6, R1, R2, R3 and R4 are defined in the Summary of the Invention; capable of inhibiting the activity of BCR-ABL1 and mutants thereof. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancers.
- -
-
Paragraph 00299-00300
(2013/12/03)
-
- COMPOUNDS FOR POROUS FILMS IN LIGHT-EMITTING DEVICES
-
Compounds useful in porous films for light extraction and/or light scattering in electronic devices, such as light-emitting devices, are described herein. These compounds may be represented by Formula 1, as described herein. [in-line-formulae]Rg5-Rg3-Rg1-Rg2-Rg4??(Formula 1)[/in-line-formulae]
- -
-
Page/Page column 18; 19
(2012/09/11)
-
- QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS
-
A compound of formula (I) wherein A, X, Y, Z, R1 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.
- -
-
Page/Page column 268
(2011/04/14)
-
- TRIS(ARYLBENZOXAZOLE)BENZENE AND TRIS(ARYLBENZTHIAZOLE)BENZENE AND DERIVATIVES THEREOF AS ORGANIC ELECTRON-TRANSPORT MATERIALS
-
A compound represented by a Formula 1: wherein Ph1, Ar1, Ar2, Ar3 Bz1, Bz2, and Bz3 are described herein. Light-emitting devices containing the compound of Formula are also described herein.
- -
-
Page/Page column 7; 8
(2011/08/22)
-
- N-ACYL ANTHRANILIC ACID DERIVATIVE OR SALT THEREOF
-
An N-acyl anthranilic acid derivative represented by general formula (1) or a salt thereof is useful for prevention or treatment of diseases associated with excessive production of collagen. (In the formula, R1 represents a carboxyl group or the like; R2 represents a hydrogen atom or the like; R3 represents an optionally substituted aryl group or the like; X1 represents a carbonyl group; X2 represents a bonding hand; X3 represents a bonding hand; X4 represents a bonding hand or the like; and A represents an optionally substituted phenyl group or the like.)
- -
-
Page/Page column 53
(2011/11/13)
-
- Catalytic syntheses of N-heterocyclic ynones and ynediones by in situ activation of carboxylic acids with oxalyl chloride
-
Breaking the bottleneck: α-Keto carboxylic acids and N-heterocyclic carboxylic acids are activated in situ with oxalyl chloride then catalytically alkynylated to give ynediones and N-heterocyclic ynones efficiently in a one-pot fashion. 5-Acylpyrazoles and 2-phenylaminopyrimidines, potentially interesting for pharmaceutical applications, are readily synthesized in concise one-pot, three-component syntheses. Copyright
- Boersch, Christina,Merkul, Eugen,Mueller, Thomas J. J.
-
supporting information; experimental part
p. 10448 - 10452
(2011/12/05)
-
- Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development
-
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H3 receptor antagonists is described. These compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
- Letavic, Michael A.,Aluisio, Leah,Atack, John R.,Bonaventure, Pascal,Carruthers, Nicholas I.,Dugovic, Christine,Everson, Anita,Feinstein, Mark A.,Fraser, Ian C.,Hoey, Kenway,Jiang, Xiaohui,Keith, John M.,Koudriakova, Tatiana,Leung, Perry,Lord, Brian,Lovenberg, Timothy W.,Ly, Kiev S.,Morton, Kirsten L.,Timothy Motley,Nepomuceno, Diane,Rizzolio, Michele,Rynberg, Raymond,Sepassi, Kia,Shelton, Jonathan
-
scheme or table
p. 4210 - 4214
(2010/09/04)
-
- Nicotinic acid adenine dinucleotide phosphate analogues containing substituted nicotinic acid: Effect of modification on Ca2+ release
-
Analogues of nicotinic acid adenine dinucleotide phosphate (NAADP) with substitution at either the 4- or the 5-position position of the nicotinic acid moiety have been synthesized from NADP enzymatically using Aplysia californica ADP-ribosyl cyclase or mammalian NAD glycohydrolase. Substitution at the 4-position of the nicotinic acid resulted in the loss of agonist potency for release of Ca2+-ions from sea urchin egg homogenates and in potency for competition ligand binding assays using [32P]NAADP. In contrast, several 5-substituted NAADP derivatives showed high potency for binding and full agonist activity for Ca2+ release. 5-Azido-NAADP was shown to release calcium from sea urchin egg homogenates at low concentration and to compete with [32P]NAADP in a competition ligand binding assay with an IC50 of 18 nM, indicating that this compound might be a potential photoprobe useful for specific labeling and identification of the NAADP receptor.
- Jain, Pooja,Slama, James T.,Perez-Haddock, Leroy A.,Walseth, Timothy F.
-
scheme or table
p. 7599 - 7612
(2011/02/22)
-
- PHOSPHATIDYLINOSITOL 3 KINASE INHIBITORS
-
Provided are compounds according to Formula (I), or stereoisomer, prodrug, polymorph, or pharmaceutically acceptable salt forms thereof, wherein X, Y, R1, R6 , R7, and R8 are as defined, which compounds are effective inhibitors of PI3-kinase and/or other medically and clinically relevant kinases. Also provided are pharmaceutical compositions and methods of using the compounds and compositions as PB -kinase and kinase inhibitors. More particularly, the compounds of the invention provide treatments and therapeutics for human diseases regulated by, or associated with, the activity of, PI3-kinases and/or protein kinases, or mutant or variant forms thereof.
- -
-
Page/Page column 128-129
(2010/01/12)
-
- BICYCLIC HETEROARYL COMPOUNDS AND THEIR USE AS KINASE INHIBITORS
-
Phosphatidylinositol (PI) 3-kinase inhibitor compounds, their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
- -
-
Page/Page column 88
(2009/03/07)
-
- SUBSTITUTED PYRIDYL AMIDE COMPOUNDS AS MODULATORS OF THE HISTAMINE H3 RECEPTOR
-
Certain substituted pyridyl amide compounds are histamine H3 receptor modulators useful in the treatment of histamine H3 receptor-mediated diseases.
- -
-
Page/Page column 8
(2009/05/28)
-
- Selective Ligands for the Neuronal Nicotinic Receptors and Uses Thereof
-
The present application describes selective ligands of formula (I) for neuronal nicotinic receptors (NNRs), more specifically for the α4β2 NNR subtype, compositions thereof, and methods of using the same, wherein X, R1, X, R2, R3, L1, m, n, p, and q are defined in the specification.
- -
-
Page/Page column 24
(2009/12/04)
-
- Structure-activity relationships comparing N-(6-methylpyridin-yl)- substituted aryl amides to 2-methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4-(substituted-arylethynyl)thiazoles as novel metabotropic glutamate receptor subtype 5 antagonists
-
The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20-23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range = 2-5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.
- Kulkarni, Santosh S.,Zou, Mu-Fa,Cao, Jianjing,Deschamps, Jeffrey R.,Rodriguez, Alice L.,Conn, P. Jeffrey,Newman, Amy Hauck
-
experimental part
p. 3563 - 3575
(2010/04/05)
-
- Fast and efficient access to a family of multifunctional 1,3,5-trisubstituted piperidines
-
A collection of new 1,3,5-trisubstituted piperidines has been synthesized starting from the commercially available 5-bromonicotinic acid. A unified, diastereoselective strategy allows the controlled access to both cis and trans stereochemistries. The heterocyclic compounds thus prepared bear multiple functional groups suitable for structural diversification and combichem protocols. Copyright Taylor & Francis Group, LLC.
- Diaz, Jose Luis,Fernandez-Forner, Dolors,Bach, Jordi,Lavilla, Rodolfo
-
experimental part
p. 2799 - 2813
(2009/04/11)
-
- Identification and structure-activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists
-
The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPγS35 functional assay.
- Allen, Daniel R.,Bolt, Amanda,Chapman, Gayle A.,Knight, Roland L.,Meissner, Johannes W.G.,Owen, David A.,Watson, Robert J.
-
p. 697 - 701
(2008/12/21)
-
- SELECTIVE KINASE INHIBITORS BASED ON PYRIDINE SCAFFOLD
-
There is described a compound of the general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms, and isomeric forms thereof, a pharmaceutical composition comprising a compound of general formula (I), a method for the treatment of a tyrosine kinase-associated disease state and a method of suppressing the immune system using a compound of general formula (I).
- -
-
Page/Page column 36-37
(2010/11/27)
-
- SIX-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS
-
The present invention provides compounds of Formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, R3 and R11 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
- -
-
Page/Page column 97
(2008/06/13)
-
- Unusual sterically controlled regioselective lithiation of 3-bromo-5-(4,4′-dimethyl)oxazolinylpyridine. Straightforward access to highly substituted nicotinic acid derivatives
-
(Chemical Equation Presented) Lithiation of 5-bromonicotinic acid protected as secondary or tertiary amide as well as (4,4′-dimethyl)oxazoline with lithium amides is reported. The unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4′-dimethyl)oxazolinylpyridine using LTMP versus LDA was observed, providing a new route to substituted nicotinic acid scaffolds. The methodology was applied to the synthesis of novel C-4 and C-6 arylated 5-bromonicotinic acids.
- Robert, Nicolas,Bonneau, Anne-Laure,Hoarau, Christophe,Marsais, Francis
-
p. 6071 - 6074
(2007/10/03)
-
- GLYCAN ANALYSIS USING DEUTERATED GLUCOSE
-
Novel Methods and apparatuses are provided for use in identifying glucose metabolic products and determining metabolic flux by administering D7-glucose to a subject.
- -
-
Page/Page column 54; 56
(2008/06/13)
-
- AMIDE DERIVATIVE AND MEDICINE
-
The present invention is directed to an amide derivative having excellent BCR-ABL tyrosine kinase inhibitory activity, or a salt thereof. The present invention provides an amide derivative represented by the following general formula [1]: (wherein R1 represents -CH2-R11, etc.; R2 represents alkyl, halogen, haloalkyl, etc.; R3 represents hydrogen, etc.; Het1 represents a group of the formula [6] as above, etc.; and Het2 represents pyrimidinyl, etc.), or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an active ingredient. The compound of the present invention is useful as a BCR-ABL tyrosine kinase inhibitor.
- -
-
Page/Page column 33
(2010/11/23)
-
- 3-(2-Aminoethyl)pyridine analogs as α4β2 nicotinic cholinergic receptor ligands
-
An examination of several 3-(2-aminoethyl)pyridine analogs suggests that they likely orient at α4β2 nicotinic cholinergic receptors in a different fashion than their correspondingly substituted nicotine analogs.
- Dukat, Malgorzata,Ramunno, Anna,Banzi, Rita,Damaj, M. Imad,Martin, Billy,Glennon, Richard A.
-
p. 4308 - 4312
(2007/10/03)
-
- AMIDE DERIVATIVE
-
The present invention provides an amide derivative represented by the following general formula (1): wherein R1 represents a saturated cyclic amino group, R2 represents alkyl, halogen or haloalkyl, R3 represents hydrogen or halogen, Het 2 represents pyridyl or pyrimidinyl, and Het 1 represents a group of the formula [6], or a salt thereof, and a pharmaceutical composition comprising the same as an active ingredient. The compound of the present invention is useful as a BCR-ABL tyrosine kinase inhibitor.
- -
-
Page/Page column 17
(2008/06/13)
-
- Syntheses of substituted pyridines, quinolines and diazines via palladium-catalyzed cross-coupling of aryl Grignard reagents
-
The palladium-catalyzed cross-coupling reactions between arylmagnesium halides (phenylmagnesium chloride, mesitylmagnesium bromide, 4-(methoxycarbonyl)phenylmagnesium chloride and 4-cyanophenylmagnesium chloride) and halopyridines allowed the synthesis of substituted pyridines. Owing to the remarkably mild conditions used (often below 0°C), the reaction could be extended to the use of functionalized halopyridines, haloquinolines and halodiazines.
- Bonnet, Véronique,Mongin, Florence,Trécourt, Fran?ois,Quéguiner, Guy,Knochel, Paul
-
p. 4429 - 4438
(2007/10/03)
-
- Catalytic asymmetric synthesis and asymmetric autocatalysis of chiral 5,5'-(3,3'-bipyridyl)-dialkanediol
-
(S,S)-(-)-5,5'-(3,3'-Bipyridyl)dialkanediols (5a, b) with up to 98.6% e.e. was synthesized by the enantioselective addition of dialkylzincs to 3,3'-bipyridine-5,5'-dicarbaldehyde (4) using N,N-dipropylnorephedrine as a chiral catalyst. Chiral diol (5a) was found to work as an asymmetric autocatalyst in the enantioselective addition of diisopropylzinc to aldehyde (4).
- Tanji, Shigehisa,Nakao, Tomohiko,Sato, Itaru,Soai, Kenso
-
p. 2183 - 2189
(2007/10/03)
-
- Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain.
-
A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.
- McElhinney,Donnelly,McCormick,Kelly,Watson,Rafferty,Elder,Middleton,Willington,McMurry,Margison
-
p. 5265 - 5271
(2007/10/03)
-
- Synthesis of [17-14C] nicergoline
-
The synthesis of 1,6-dimethyl-8β-(5-bromonicotinoyl-[14C]oxymethyl-10α-methoxy-ergoline ([17-14C] nicergoline) is reported. A five-step route starting from the addition of potassium [14C] cyanide 2 to 1,6-dimethyl-8β-chloro-10α-methoxy-ergoline 1 yielded the expected [17-14C] nicergoline, 97% radiochemically pure, with a specific activity of 2.23 GBq/mmol. The overall radiochemical yield was about 10% from 2.
- Angiuli,Fontana,Dostert
-
p. 331 - 337
(2007/10/03)
-
- The chemistry of benzothiadiazole plant activators
-
Systemic Acquired Resistance (SAR) is an inducible resistance mechanism in plants that, together with other defence mechanisms, provides broadspectrum and long-lasting disease control. With novel screening techniques the benzo[1,2,3]thiadiazole-7-carboxylic acid derivatives have been identified as a new class of chemicals which stimulate the plant's own defence mechanisms. The synthesis and biological activities of various benzo[1,2,3]thiadiazoles and related structures are described. S-Methyl benzo[1,2,3]thiadiazole-7-carbothioate is the first synthetic chemical 'plant activator' that has been developed for this novel disease control concept.
- Kunz,Schurter,Maetzke
-
p. 275 - 282
(2007/10/03)
-
- A General Synthesis of 5-Arylnicotinates
-
Arylboronic acids have been found to couple efficiently with 5-bromonicotinates to yield 5-arylnicotinates.The reaction is considerably more sensitive to steric inhibition in the arylboronic acid component than in the pyridyl bromide 4.The dianion salt of the boronic acid is implicated as the reactive intermediate responsible for the facile coupling reaction.Pure arylboronic acids are best prepared by using triisopropyl borate as the transmetalating agent.
- Thompson, Wayne J.,Gaudino, John
-
p. 5237 - 5243
(2007/10/02)
-
