- Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
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EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Her
- Hao, Yongjia,Wang, Xia,Zhang, Tao,Sun, Deheng,Tong, Yi,Xu, Yuqiong,Chen, Haiyang,Tong, Linjiang,Zhu, Lili,Zhao, Zhenjiang,Chen, Zhuo,Ding, Jian,Xie, Hua,Xu, Yufang,Li, Honglin
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Read Online
- Cannabinoid receptor light-operated ligand and preparation method and application thereof
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The invention relates to the technical field of biology, in particular to a novel cannabinoid receptor light-operated ligand and a preparation method and application thereof. Disclosed is the cannabinoid receptor light-operated ligand or the isomer prodrug, the solvate and the pharmaceutically acceptable salt of the cannabinoid receptor light-operated ligand, wherein the structural formula of thecannabinoid receptor light-operated ligand is A-linker-B; A is a transmembrane domain ligand structure, and B is a light-operated element; Linker is a subunit which is linear and has no activity on acannabinoid receptor light-operated ligand. According to the invention, the cannabinoid receptor ligand is integrated with azobenzene through a proper connector, so that the ligand configuration is changed under an illumination condition, and the activation or inhibition state of the cannabinoid receptor is regulated and controlled.
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Paragraph 0066; 0073-0078
(2021/01/24)
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- SARs of a novel series of s-triazine compounds targeting vimentin to induce methuotic phenotype
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Herein, we describe the design, synthesis and structure?activity relationships of a series of novel s-triazine compounds can induce methuotic phenotype in various types of cancer cells. (E)-1-(4-Chlorophenyl)-3-(4-((4-morpholino-6-styryl-1,3,5-triazine-2-yl)amino)phenyl)urea, compound V6, exhibited a striking methuotic phenotype with a minimal effective concentration of less than 10 nM in U87 glioblastoma cells. Based on structure?activity relationship studies, we designed and synthesized an active probe P1 that retained the full potential of V6 in inducing the methuotic phenotype in U87 glioblastoma cells. Using this probe following affinity-based proteomic profiling strategy, we identified vimentin as the specific target protein of compound V6. Molecular docking revealed that V6 can form hydrogen bonds with vimentin at 273R and 276Y in its rod domain.
- Zhang, Lei,Qu, Zhipeng,Wu, Jianping,Yao, Shining,Zhang, Qingqing,Zhang, Tao,Mo, Lian,Yao, Qizheng,Xu, Ying,Chen, Ruihuan
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- Compound with B lymphocyte tyrosine kinase inhibitory activity and application thereof
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The invention belongs to the technical field of medicines, and particularly provides a compound with B lymphocyte tyrosine kinase inhibitory activity and application thereof. The compound is selected from at least one of nine (T1-T9) compounds. The compound with B lymphocyte tyrosine kinase inhibitory activity can effectively and selectively inhibit BLK activity, and can be used as an inhibitor or a drug.
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Paragraph 0018-0020
(2021/08/11)
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- Various located urea and schiff-base bifunctional derivatives: Their gelation and Zn2+ sensing behaviors
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The efficient combination of various moieties is helpful to develop organic functional molecules. Herein, three of urea and Schiff-base bifunctional derivatives (OG, MG and PG) were prepared from o/m/p-diaminobenzene respectively. Benefitting from the urea and Schiff-base, these derivatives revealed satisfactory gelation capacity. However, the various locations of urea and imine paved them markedly different assembly performances during the gel formation. Additionally, these functional molecules displayed obvious “off-on” fluorescence sensing behaviors towards Zn2+ in solution ascribing to the imine and neighbor phenolic hydroxyl, among which the MG displayed the best Zn2+ selectivity. Crucially, the MG also realized Zn2+ probing at cellular level and its gel gave a visual detection via the gel-sol transition.
- Chen, Yu,Lei, Zhimei,Liu, Jie,Sun, He-Lue,Xing, Li-Juan,Yu, Haitao,Zhang, Xin
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- Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools
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Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.
- Hu, Tao,Hua, Tian,Li, Fei,Liu, Zhi-Jie,Makriyannis, Alexandros,Stevens, Raymond C.,Tao, Houchao,Tian, Cuiping,Xie, Linshan,Xu, Yueming,Xue, Dongxiang,Zhao, Fei,Zhao, Simeng,Zhao, Suwen,Zheng, Guoxun,Zhong, Guisheng,Zhou, Fang
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p. 13752 - 13765
(2021/09/20)
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- SUBSTITUTED AMIDE COMPOUNDS USEFUL AS FARNESOID X RECEPTOR MODULATORS
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Disclosed are compounds of Formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is: (i) halo, cyano, hydroxyl, NRxRx, C(O)OH, C(O)NH2, C1-6 alkyl substituted with zero to 6 R1a, or P(O)R1cR1c; or (ii) L R1; and A, X1, X2, X3, X4, Z1, Z2, R1, R1a, R1c, R2, R3a, R3b, Rx, L, a, b, and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of farnesoid X receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression
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Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.
- Mehndiratta, Samir,Lin, Mei-Hsiang,Wu, Yi-Wen,Chen, Chun-Han,Wu, Tung-Yun,Chuang, Kuo-Hsiang,Chao, Min-Wu,Chen, Yi-Ying,Pan, Shiow-Lin,Chen, Mei-Chuan,Liou, Jing-Ping
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- Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression
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Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC50 = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against receptor tyrosine kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.
- Lakkaniga, Naga Rajiv,Zhang, Lingtian,Belachew, Binyam,Gunaganti, Naresh,Frett, Brendan,Li, Hong-yu
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- Bruton's tyrosine kinase inhibitor
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The invention discloses a compound with a general formula (I), wherein the compound is capable of inhibiting Btk, and the groups are disclosed in the invention. The compound can be used for treating autoimmune diseases, heterologous immunization diseases, cancers, or thromboembolism diseases. The invention also discloses a pharmaceutical composition containing the compound represented by formula (I). The Bruton's tyrosine kinase inhibitor is capable of inhibiting the activity of Bruton's tyrosine kinas through covalent binding such as a covalent reversible mode.
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Paragraph 0115-0117
(2019/03/26)
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- Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking
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Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of 0.58 and 0.23 μM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.
- Zhao, Yongqiang,Liu, Feifei,He, Guojing,Li, Ke,Zhu, Changcheng,Yu, Wei,Zhang, Conghai,Xie, Mingjin,Lin, Jun,Zhang, Jihong,Jin, Yi
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- Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat
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Specifically blocking more than one oncogenic pathway simultaneously in a cancer cell with a combination of different drugs is the mainstay of the majority of cancer treatments. Being able to do this via two targeted pathways without inducing side effects through a general mechanism, such as chemotherapy, could bring benefit to patients. In this work we describe a new dual inhibitor of the JAK-STAT and HDAC pathways through designing and developing two types of molecule based on the JAK2 selective inhibitor XL019 and the pan-HDAC inhibitor, vorinostat. Both series of compounds had examples with low nanomolar JAK2 and HDAC1/6 inhibition. In some cases good HDAC1 selectivity was achieved while retaining HDAC6 activity. The observed potency is explained through molecular docking studies of all three enzymes. One example, 69c had 16–25 fold selectivity against the three other JAK-family proteins JAK1, JAK3 and TYK2. A number of compounds had sub-micromolar potencies against a panel of 4 solid tumor cell lines and 4 hematological cell lines with the most potent compound, 45h, having a cellular IC50 of 70 nM against the multiple myeloma cell line KMS-12-BM. Evidence of both JAK and HDAC pathway inhibition is presented in Hela cells showing that both pathways are modulated. Evidence of apoptosis with two compounds in 4 sold tumor cell lines is also presented.
- Chu-Farseeva, Yu-yi,Mustafa, Nurulhuda,Poulsen, Anders,Tan, Eng Chong,Yen, Jeffrey J.Y.,Chng, Wee Joo,Dymock, Brian W.
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p. 593 - 619
(2018/10/02)
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- Design, Synthesis, and Biological Evaluation of Pyrimido[4,5- d]pyrimidine-2,4(1 H,3 H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
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First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFRL858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that 20g might be used as a promising lead compound for further structural optimization as potent and selective EGFRL858R/T790M inhibitors.
- Hao, Yongjia,Lyu, Jiankun,Qu, Rong,Tong, Yi,Sun, Deheng,Feng, Fang,Tong, Linjiang,Yang, Tingyuan,Zhao, Zhenjiang,Zhu, Lili,Ding, Jian,Xu, Yufang,Xie, Hua,Li, Honglin
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p. 5609 - 5622
(2018/06/25)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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The invention relates to the field of medicine, discloses new nitrogen heterocyclic derivatives, preparation method thereof and as medicament in particular as the treatment and prevention of treating tissue fibrosis of the medicament. The invention also discloses a pharmaceutically acceptable compound of the present invention comprise a pharmaceutical composition and methods for using the composition for the treatment of the human or animal tissue fibrosis of diseases, in particular for treating the human or animal renal interstitial fibrosis, glomerular sclerosis, hepatic fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, after the operation of adhering, benign prostate hypertrophy, bone-myocardial, scleroderma, multiple sclerosis, pancreas fibrosis, liver cirrhosis, myosarcoma, neurofibromatosis, interstitial pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis disease in use. (by machine translation)
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- BTK INHIBITOR
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Provided are a series of BTK inhibitors, and specifically disclosed are a compound, pharmaceutically acceptable salt thereof, tautomer thereof or prodrug thereof represented by formula (I), (II), (III) or (IV).
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Paragraph 0581-0582
(2017/11/16)
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- Development of first lead structures for phosphoinositide 3-kinase-c2γ inhibitors
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The importance of complete elucidation of the biological functions of phosphoinositide 3-kinases (PI3K) was realized years ago. They generate 3-phosphoinositides, which are known to function as important second messengers in many inter- and intracellular signaling pathways. However, the functional role of class II PI3Ks is still unclear. Herein, we describe the synthesis of a panel of compounds that were tested against all eight mammalian PI3K-isoforms. We found inhibitors with some selectivity for class II PI3K-C2γ and also compounds with preferred inhibition of class II PI3K-C2β, providing structural leads to develop selective tool compounds.
- Freitag, Anne,Prajwal, Prajwal,Shymanets, Aliaksei,Harteneck, Christian,Nürnberg, Bernd,Sch?chtele, Christoph,Kubbutat, Michael,Totzke, Frank,Laufer, Stefan A.
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supporting information
p. 212 - 221
(2015/03/03)
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- Nitrogenous Heterocyclic Derivatives And Their Application In Drugs
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The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
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Paragraph 0580
(2015/03/31)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
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Paragraph 00315
(2014/02/15)
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- INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
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The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provide
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Paragraph 00363
(2014/05/07)
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- KINASE INHIBITOR AND METHOD FOR TREATMENT OF RELATED DISEASES
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Disclosed is a compound of (aminophenylamino) pyrimidyl benzamides and a synthesis method thereof. The compound has Btk-inhibition activity and can be used to treat autoimmune diseases, heteroimmune diseases, cancers or thromboembolic diseases.
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Paragraph 0078; 0079
(2014/09/17)
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- KINASE INHIBITOR AND METHOD FOR TREATMENT OF RELATED DISEASES
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Disclosed is a compound of (aminophenylamino) pyrimidyl benzamides and a synthesis method thereof. The compound has Btk-inhibition activity and can be used to treat autoimmune diseases, heteroimmune diseases, cancers or thromboembolic diseases.
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Paragraph 0106-0107
(2014/09/29)
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- Controllable self-assembly of amphiphilic macrocycles into closed-shell and open-shell vesicles, nanotubes, and fibers
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Depending on functional groups, amphiphilic hexaamide macrocycles self-assemble into closed-shell and open-shell vesicles in polar solvents. In the presence of water, open-shell vesicles morph into closed-shell vesicles, whereas acidification of the mediu
- Mitra, Atanu,Panda, Dillip K.,Corson, Lucas J.,Saha, Sourav
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supporting information
p. 4601 - 4603
(2013/06/05)
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- Syntheses and electronic structure of bimetallic complexes containing a flexible redox-active bridging ligand
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The new ligand L1, 1-N,1-N-bis(pyridine-2-ylmethyl)-3-N- (pyridine-2-ylmethylidene)benzene-1,3-diamine, was synthesized as a platform for the study of bimetallic complexes containing redox-active ligands. The asymmetric L1 contains a redox-active α-iminopyridine unit bridged to redox-inert bis(2-pyridylmethyl)amino counterpart and offers two distinct coordination sites. The coordination chemistry of L1 with Fe, Cu, and Zn was examined. Reaction with zinc afforded the asymmetric binuclear complex [(L1)Zn2Cl4] (1), whereas the symmetric [(L1)2Fe2(OTf)2](OTf) 2 (2) and [(L1)2Cu2](OTf) 4 (3) were isolated in reactions with iron and copper. Both metal-and ligand-centered redox processes are available to the series of metal compounds. EPR and Moessbauer spectroscopy and magnetic susceptibility studies establish that both 2 and 3 are paramagnetic; the vanishingly small ferromagnetic interaction produces decoupled high-spin FeII (S = 2) ions in 2. DFT calculations provide further insight into the nature of the exchange interactions in the dimeric systems.
- Lindsay, Stacey,Lo, Siu K.,Maguire, Oliver R.,Bill, Eckhard,Probert, Michael R.,Sproules, Stephen,Hess, Corinna R.
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p. 898 - 909
(2013/03/13)
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- Novel 5-anilinoquinazoline-8-nitro derivatives as inhibitors of VEGFR-2 tyrosine kinase: Synthesis, biological evaluation and molecular docking
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Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoquinazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibitors with in vitro IC 50 values in the submicromolar range (compound 6f, IC50 12.0 nM), but showed a weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were studied using molecular docking studies. The Royal Society of Chemistry 2013.
- Xi, Liang,Zhang, Jian-Qiang,Liu, Zhi-Cheng,Zhang, Ji-Hong,Yan, Ju-Fang,Jin, Yi,Lin, Jun
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p. 4367 - 4378
(2013/08/23)
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- Carbamic acid 2-trimethylsilylethyl ester as a new ammonia equivalent for palladium-catalyzed amination of aryl halides
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Carbamic acid 2-trimethylsilylethyl ester (Teoc-NH2) serves as an ammonia equivalent in the palladium-catalyzed amination of aryl bromides and aryl chlorides. Anilines with sensitive functional groups can be readily prepared using these amine derivatives.
- Mullick, Dibakar,Anjanappa, Prakash,Selvakumar, Kumaravel,Ruckmani, Kandasamy,Sivakumar, Manickam
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supporting information; experimental part
p. 5984 - 5987
(2010/11/21)
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- An efficient kilogram-scale synthesis of N,N2 -bis(4,6-disubstituted 1,3,5-triazin-2-yl)-4-aminophenetylamine
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A practical large-scale synthesis was developed for the preparation of N,N2 -bis(4,6-disubstituted 1,3,5-triazin-2-yl)-4-aminophenethylamine derivatives exemplified by compound 2. This route is a sixstep procedure starting from commercially available cyan
- Duceppe, Jean-Simon,Perron, Valerie,Cloutier, Josee,Penney, Christopher,Zacharie, Boulos
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experimental part
p. 1156 - 1160
(2010/04/22)
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- Helix persistence and breakdown in oligoureas of metaphenylenediamine: Apparent diastereotopicity as a spectroscopic marker of helix length in solution
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Oligomeric ureas derived from m-phenylenediamine with chain lengths of up to seven urea linkages were made by iterative synthetic pathways. Three families were synthesized: 4 and 20, bearing a terminal chiral sulfinyl group; 24, bearing a terminal rotatio
- Clayden, Jonathan,Lemiegre, Loic,Morris, Gareth A.,Pickworth, Mark,Snape, Timothy J.,Jones, Lyn H.
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supporting information; experimental part
p. 15193 - 15202
(2009/03/12)
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- Selective neuronal nitric oxide synthase inhibitors
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Peptidomimetic compositions for selective inhibition of neuronal nitric oxide synthase.
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Page/Page column 30
(2009/01/24)
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- THIOUREA COMPOUNDS
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This invention relates to thiourea compounds described herein. These thiourea compounds can be used to treat hepatitis C virus infection.
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Page/Page column 45-46
(2008/06/13)
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- Metasubstituted thiazolidinones, their manufacture and use as a drug
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This invention involves thiazolidinone of general formula (I) and its creation and use as inhibitors of polo like kinase (PLK) for the treatment of various diseases.
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Page/Page column 40
(2010/11/25)
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- Novel, achiral 1,3,4-benzotriazepine analogues of 1,4-benzodiazepine-based CCK2 antagonists that display high selectivity over CCK1 receptors
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A series of 1,3,4-benzotriazepine-based CCK2 antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine- based CCK2 antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK2 receptors to the earlier molecules and are highly selective over CCK1 receptors.
- McDonald, Iain M.,Austin, Carol,Buck, Ildiko M.,Dunstone, David J.,Griffin, Eric,Harper, Elaine A.,Hull, Robert A. D.,Kalindjian, S. Barret,Linney, Ian D.,Low, Caroline M. R.,Pether, Michael J.,Spencer, John,Wright, Paul T.,Adatia, Trushar,Bashall, Alan
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p. 2253 - 2261
(2007/10/03)
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- PURINE DERIVATIVES AND THEIR USE FOR TREATMENT OF AUTOIMMUNE DISEASES
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Compounds useful in the treatment of autoimmune disease are described by the following general formula (I): n = 0-2 m = 0-2 m is not necessarily equal to n; where R1, R3 = NH2, F, Cl, C1-C4 alkoxy or
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Page/Page column 22; 23
(2008/06/13)
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- N-salicylideneanilines: Tautomers for formation of hydrogen-bonded capsules, clefts, and chains
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The synthesis, characterization, and solid-state structures of new salicylaldimines are reported. Bis(N-salicylideneaniline)s (BSANs) and tris(N-salicylideneaniline)s (TSANs) are sterically encumbered compounds featuring a central six-membered ring in the
- Sauer, Marc,Yeung, Charles,Chong, Jonathan H.,Patrick, Brian O.,MacLachlan, Mark J.
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p. 775 - 788
(2007/10/03)
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- SUGAR CHAIN LIGAND COMPOSITE AND METHOD OF ANALYZING PROTEIN WITH THE LIGAND COMPOSITE
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A novel ligand conjugate which is effectively utilizable for analyzing a function of a protein; a ligand-supporting object; and a method of analyzing a protein. The ligand conjugate has a structure which comprises: a linker compound having a structure represented by the following General Formula (1): (wherein n and p each is an integer of 0 to 6) in which X is a structure comprising one, two, or three hydrocarbon derivative chains which have an aromatic amino group at the end and may have a carbon-nitrogen bond in the main chain, Y is a hydro-carbon structure containing one or more sulfur atoms, and Z is a straight-chain structure comprising a carbon-carbon bond or carbon-oxygen bond; and a sugar which has a reducing end and is bonded to the linker compound through the aromatic amino group.
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Page/Page column 19-20
(2010/11/24)
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- THIOPHENE HETEROARYL AMINES
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The present invention relates to thiophene heteroaryl amines and their pharmaceutically acceptable salts that modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer. Formula (I).
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Page/Page column 49
(2010/02/14)
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- MULTIPURPOSE LINKER COMPOUNDS AND LIGANDS AND PROCESS FOR PRODUCING THE SAME
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A versatile linker compound has a structure represented by following general formula (1), wherein Y has a structure represented by O or NH, and X has a structure serving as a multi-branched moiety including four hydrocarbon derivative chains each of which has an aromatic amino group at an end thereof, and may or may not have a carbon-nitrogen bond in a backbone thereof. With the versatile linker compound, sugar molecules can be two-dimensionally arranged on a surface of a protein-analyzing supporter with high reproducibility. Also, a ligand includes the versatile linker compound and a sugar molecule introduced thereinto.
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Page/Page column 16
(2010/02/12)
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- SUBSTITUTED 2-CARBONYLAMINO-6-PIPERIDINAMINOPYRIDINES AND SUBSTITUTED 1-CARBONYLAMINO-3-PIPERIDINAMINOBENZENES AS 5-HT1F AGONISTS
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ABSTRACT The present invention relates to compounds of formula I: (I) or a pharmaceutically acceptable acid addition salt thereof, where; X is C(R3c= or N=; R1 is C2-C6 alkyl, substituted C2-C6/
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Page/Page column 28-29
(2010/02/11)
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- Pharmaceutical uses and synthesis of nicotinamides
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A compound of the formula and pharmaceutically acceptable salts thereof, wherein R1is selected from (R3)C(═O)—N(R4)— and (R3)(R4)N—C(═O)—; R2is selected from —OR5and —N(R5)(R6); n is 0, 1, 2 or 3; X is selected from oxygen and sulfur; and R3, R4, R5and R6are independently selected from hydrogen, alkyl, heteroalkyl, aryl, aryl(akylene), heteroaryl, heteroaryl(alkylene), carbocycle, carbocycle(alkylene), heterocycle, and heterocycle(alkylene); as well as pharmaceutical compositions containing said compound. The compounds and compositions are useful in, for example, the treatment of inflammatory events in an animal subject.
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Page/Page column 28
(2010/02/08)
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- Aromatic reduced amide bond peptidomimetics as selective inhibitors of neuronal nitric oxide synthase
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Nitric oxide synthase inhibitors could act as important therapies for disorders arising from overstimulation or overexpression of individual nitric oxide synthase (NOS) isoforms. But preservation of physiologically important nitric oxide functions require the use of isoform-selective inhibitors. Recently we reported reduced amide bond pseudodipeptide analogues as potent and selective neuronal nitric oxide synthase (nNOS) inhibitors (Hah, J.-M.; Roman, L. J.; Martasek, P.; Silverman, R. B. J. Med. Chem. 2001, 44, 2667-2670). To increase the lipophilicity a series of aromatic, reduced amide bond analogues (6-25) were designed and synthesized as potential selective nNOS inhibitors. The hypothesized large increase in isoform selectivity of nNOS over inducible NOS was not obtained in this series. However, the high potency with nNOS as well as high selectivity of nNOS over endothelial NOS was retained in some of these compounds (15, 17, 21), as well as good selectivity over inducible NOS. The most potent nNOS inhibitor among these compounds is N-(4S)-{4-amino-5-[2-(2-aminoethyl)-phenylamino]-pentyl}-N′- nitroguanidine (17) (Ki = 50 nM), which also shows the highest selectivity over eNOS (greater than 2100-fold) and 70-fold selectivity over iNOS. Further modification of compound 17 should lead to even more potent and selective nNOS inhibitors.
- Hah, Jung-Mi,Martásek, Pavel,Roman, Linda J.,Silverman, Richard B.
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p. 1661 - 1669
(2007/10/03)
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- Selective neuronal nitric oxide synthase inhibitors
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Peptidomimetic compositions for selective inhibition of neuronal nitric oxide synthase.
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- N-aryl N′-hydroxyguanidines, a new class of NO-donors after selective oxidation by nitric oxide synthases: Structure-activity relationship
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The formation of nitric oxide (NO) was followed during the oxidation of 37 N-hydroxyguanidines or related derivatives, including 18 new N-aryl N′ -hydroxyguanidines, by recombinant inducible nitric oxide synthase (NOS II). Several N-aryl N′-hydroxyguanidines bearing a relatively small, electron-donating para subtituent, such as H, F, Cl, CH3, OH, OCH3, and NH2, led to NO formation rates between 8 and 41% of that of NO formation from the natural NOS substrate, Nω-hydroxy-L-arginine (NOHA). The characteristics of these reactions were very similar to those previously reported for the oxidation of NOHA by NOS: (i) the strict requirement of NOS containing (6R)-5,6,7,8-tetrahydro-L-biopterin, reduced nicotinamide adenine dinucleotide phosphate, and O2 for the oxidation to occur, (ii) the formation of NO and the corresponding urea in a 1:1 molar ratio, and (iii) a strong inhibitory effect of the classical NOS inhibitors such as Nω-nitro-L-arginine and S-ethyl-iso-thiourea. Structure-activity relationship studies showed that two structural factors are crucial for NO formation from compounds containing a C=NOH function. The first one is the presence of a monosubstituted N-hydroxyguanidine function, since disubstituted N-hydroxyguanidines, amidoximes, ketoximes, and aldoximes failed to produce NO. The second one is the presence of a N-phenyl ring bearing a relatively small, not electron-withdrawing para substituent that could favorably interact with a hydrophobic cavity close to the NOS catalytic site. The kcat value for NOS II-catalyzed oxidation of N-parafluorophenyl N′-hydroxyguanidine was 80% of that found for NOHA, and its kcat/Km value was only 9-fold lower than that of NOHA. Interestingly, the Km value found for NOS II-catalyzed oxidation of N-(3-thienyl) N′-hydroxyguanidine was 25 μM, almost identical to that of NOHA. Recombinant NOS I and NOS III also oxidize several N-aryl N′-hydroxyguanidines with the formation of NO, with a clearly different substrate specificity. The best substrates of the studied series for NOS I and NOS III were N-(para-hydroxyphenyl) and N-(meta-aminophenyl) N′-hydroxyguanidine, respectively. Among the studied compounds, the para-chlorophenyl and paramethylphenyl derivatives were selective substrates of NOS II. These results open the way toward a new class of selective NO donors after in situ oxidation by each NOS family.
- Renodon-Cornière, Axelle,Dijols, Sylvie,Perollier, Céline,Lefevre-Groboillot, David,Boucher, Jean-Luc,Attias, Roger,Sari, Marie-Agnes,Stuehr, Dennis,Mansuy, Daniel
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p. 944 - 954
(2007/10/03)
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- NOVEL AMIDE COMPOUNDS
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A compound of the formula (I):R1-A-X-NHCO-Y-R2 ???whereinR1 is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,R2 is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,A is a group of the formula:-(CH2)t-(O)m- or in which R3 and R4 are each hydrogen or linked together to form imino,R5 is hydrogen or lower alkyl,t is 0, 1 or 2,p, m and n are each 0 or 1,X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,Y is bond, lower alkylene, or lower alkenylene, and a salt thereof.
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- Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2- dihydropyridono[5,6-g]quinolines
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A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR- mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure - activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.
- Hamann, Lawrence G.,Higuchi, Robert I.,Zhi, Lin,Edwards, James P.,Wang, Xiao-Ning,Marschke, Keith B.,Kong, James W.,Farmer, Luc J.,Jones, Todd K.
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p. 623 - 639
(2007/10/03)
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- N-phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: Structure-activity studies and demonstration of in vivo activity
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Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3- (aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2- furanylamidine (77) (K(i-nNOS) = 0.006 μM; K(i-eNOS) = 0.35 μM; K(i-iNOS) = 0.16 μM). Finally, α-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (K(i- nNOS) = 0.011 μM; K(i-eNOS) = 1.1 μM; K(i-iNOS) = 0.48 μM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.
- Collins, Jon L.,Shearer, Barry G.,Oplinger, Jeffrey A.,Lee, Shuliang,Garvey, Edward P.,Salter, Mark,Duffy, Claire,Burnette, Thimysta C.,Furfine, Eric S.
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p. 2858 - 2871
(2007/10/03)
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- Self-Assembly of Zinc Porphyrins around the Periphery of Hydrogen-Bonded Aggregates That Bear Imidazole Groups
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This paper describes the preparation and characterization of four aggregates that are based on the rosette of derivatives of isocyanuric acid (CA) and melamine (M). These aggregates comprise a trismelamine, hub(MIm)3, that presents imidazole groups around its periphery; these imidazoles organize zinc tetraphenyl porphyrin (ZnTPP) by coordination of the imidazole to the zinc center. Aggregate 1 forms a single rosette upon mixing 1 equiv of hub(MIm)3 and 3 equiv of CA. Adding 3 equiv of ZnTPP yields 2. Aggregate 3 forms as a stacked bisrosette upon mixing 2 equiv of hub(MIm)3 and 3 equiv of bisCA. Adding 6 equiv of ZnTPP yields 4. The stoichiometries of aggregates 1-4 were obtained by titrating the trismelamines with CA and by titrating the aggregates with ZnTPP. The stoichiometry is defined as the ratio at which additional CA remains insoluble or additional ZnTPP appears as free ZnTPP in the 1H NMR spectrum. Electrospray ionization mass spectrometry (ESI-MS) is compatible with the measured stoichiometries. The structures of these aggregates were determined using variable-temperature 1H NMR spectroscopy; analogous structures were inferred for 5 and 6, the tert-butyl analogues of 1 and 2. The shapes of the traces from gel permeation chromatography (GPC) suggest that imidazole groups destabilize the aggregates when they are not involved in coordination to zinc; that is, the stability seems to be 6 ≈ 4 > 3 and 5 ≈ 2 > 1. A direct comparison of the relative stability of 1, 2, and 5 confirms the results of the GPC analysis: mixing 1 (hub(MIm)3·3CA) with the trismelamine component of 5 (hub(M)3) leads to the formation of a 3:2 mixture of 5:1. Adding ZnTPP to this solution leads to a 3:2 mixture of 5:2 with free trismelamines remaining in solution: 1 is not observed. The results of UV/vis spectroscopy are consistent with the other spectroscopic and Chromatographic results and indicate that 3 equiv of ZnTPP are organized around the periphery of 2 and at least 4 equiv around the periphery of 4.
- Simanek, Eric E.,Isaacs, Lyle,Li, Xinhua,Wang, Clay C. C.,Whitesides, George M.
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p. 8994 - 9000
(2007/10/03)
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- Molecular self-assembly through hydrogen bonding: Supramolecular aggregates based on the cyanuric acid-melamine lattice
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Reaction of the tris(melamine) derivatives hubM3 (C6H3-1,3,5-[CONHC6H4-3-N(CH 2C6H4-4-C(CH3)3)COC 6-H3-2-NHC3Ns
- Seto, Christopher T.,Whitesides, George M.
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p. 905 - 916
(2007/10/02)
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- DEVELOPMENT OF NEW DNA-BINDING AND CLEAVING MOLECULES: DESIGN, SYNTHESIS AND ACTIVITY OF A BISDIAZONIUM SALT
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The bisdiazonium compound 1 has been shown to cleave DNA at concentrations as low as 0.1 μM.Evidence is presented to indicate that 1 is binding to the minor groove of DNA, and that binding may be responsible for its effectiveness as a DNA cleaving reagent
- Arya, Dev P.,Warner, Philip M.,Jebaratnam, David J.
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p. 7823 - 7826
(2007/10/02)
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