- Selective acetylcholinesterase inhibitors derived from muscle relaxant dantrolene
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Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a therapeutic drug target for Alzheimer's disease. Thus, we focused on developing of AChE inhibitors with benzylpiperidine/piperazine moieties that are based on the dantrolene skeleton. Several derivatives showed an inhibitory activity. Among them, ortho-nitro derivative 8c showed the most potent inhibitory activity with the IC50 value of 34.2 nM. Furthermore, Lineweaver-Burk plot analysis indicated that 8c is AChE-selective inhibitor, which shows only a weak inhibitory effect on butyrylcholinesterase (BuChE) and a non-competitive inhibition.
- Aoyama, Hiroshi,Doura, Tomohiro
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Read Online
- Double-component diazeniumdiolate derivatives as anti-cancer agents
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In this study, we synthesized a series of double-component O2-aryl diazeniumdiolate (DDNO) derivatives, of which each molecule can release up to four nitric oxide molecules. These compounds showed cytotoxic activities to cancer cells, such as human leukemia, breast cancer and lung cancer. Among them, compound 1 (DDNO-1) showed the highest specific activity to human leukemia cells. It induced cell apopotosis and arrest cell cycle of G2/M phase. The JNK and p38 protein kinases were activated by compound 1 to induce cancer cell apoptosis. Compound 1 also increased pro-apoptotic Bax level, which is a same function compared to a reported NO donor, JS-K. More interestingly, it decreased the level of an anti-apoptotic member Bcl-2, which is an opposite effect compared to JS-K. Compound 1 could be developed as a new anti-cancer agent since it increases the Bax/Bcl-2 ratio to overcome the drug resistance.
- Arutla, Viswanath,Chen, Qi,Chen, Shengxi,Hu, Qiong-Ying,Ji, Xun,Khdour, Omar
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Read Online
- Design of iodinated radioligands for SPECT imaging of central human 5-HT4R using a ligand lipophilicity efficiency approach
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A series of iodinated ligands for the SPECT imaging of 5-HT4 receptors was designed starting from the previously reported hit MR-26132. We focused on the modulation of the piperidine-containing lateral chain by introducing hydrophilic groups in order to decrease the liphophilicity of the new ligands. All the synthesized compounds were tested for their binding affinities on 5-HT4Rs and based on the Ligand Lipophilicity Efficiency approach, compound 13 was further selected for radioiodination with iodine-125 and imaging experiments. Compound 13 showed its ability to displace the specific signal of the reference compound [125I]SB-207710 but no significant detection of [125I]13 was observed in vivo in SPECT experiments.
- Babin, Victor,Bouillon, Jean-Philippe,Cailly, Thomas,Davis, Audrey,Dubost, Emmanuelle,Fabis, Frédéric,Lohier, Jean-Fran?ois,Millet, Philippe,Pigrée, Gilbert,Reboul, Vincent,Tournier, Benjamin B.
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Read Online
- C10-ALKYLENE SUBSTITUTED 13-MEMBERED MACROLIDES AND USES THEREOF
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Provided are 13-membered macrolides for the treatment of infectious diseases. The 13-membered macrolides described herein are azaketolides. Also provided are methods for preparing the 13- membered macrolides, pharmaceutical compositions comprising the 13-membered macrolides, and methods of treating infectious diseases, and in particular, disease resulting from Gram negative bacteria using the disclosed macrolides. Formula (I)
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Paragraph 00305
(2020/06/10)
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- MODULATORS OF INDOLEAMINE 2,3-DIOXYGENASE
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Provided are IDO inhibitor compounds of Formula I and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and methods for their use in the prevention and/or treatment of diseases. Formula I
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- Novel multitarget-directed ligands targeting acetylcholinesterase and σ1 receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase
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Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.
- Lalut, Julien,Santoni, Gianluca,Karila, Delphine,Lecoutey, Cédric,Davis, Audrey,Nachon, Florian,Silman, Israel,Sussman, Joel,Weik, Martin,Maurice, Tangui,Dallemagne, Patrick,Rochais, Christophe
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supporting information
p. 234 - 248
(2018/11/24)
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- Novel multi target-directed ligands targeting 5-HT4 receptors with in cellulo antioxidant properties as promising leads in Alzheimer's disease
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Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aβ protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT4R agonists, and diverse antioxidant chemotypes. Interestingly, the most active compound 9g possesses a Ki of 12.7 nM towards 5-HT4R and an antioxidant activity in vitro and in cellulo.
- Lanthier, Caroline,Payan, Hugo,Liparulo,Hatat, Bérénice,Lecoutey, Cédric,Since, Marc,Davis, Audrey,Bergamini, Christian,Claeysen, Sylvie,Dallemagne, Patrick,Bolognesi, Maria-Laura,Rochais, Christophe
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- BIS-DIAZENIUMDIOLATE COMPOUNDS AS ANTI-CANCER AGENTS
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A series of double-component, bis O2-aryl diazeniumdiolate derivatives are provided, of which each molecule can release up to four nitric oxide molecules. These compounds show cytotoxic activities to cancer cells, such as human leukemia, breast cancer and lung cancer. Among them, the compound 3 showed the highest specific activity against human leukemia cells.
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Paragraph 0042; 0054; 0055
(2019/04/25)
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- Stereospecific Synthesis of E-Alkenes through Anti-Markovnikov Hydroalkylation of Terminal Alkynes
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We have developed a method for stereospecific synthesis of E-alkenes from terminal alkynes and alkyl iodides. The hydroalkylation reaction is enabled by a cooperative action of copper and nickel catalysts and proceeds with excellent anti-Markovnikov selectivity. We demonstrate the broad scope of the reaction, which can be accomplished in the presence of esters, nitriles, aryl bromides, ethers, alkyl chlorides, anilines, and a wide range of nitrogen-containing heteroaromatic compounds. Mechanistic studies provide evidence that the copper catalyst activates the alkyne by hydrocupration, which controls both the regio- and diastereoselectivity of the overall reaction. The nickel catalyst activates the alkyl iodide and promotes cross coupling with the alkenyl copper intermediate.
- Hazra, Avijit,Chen, Jason,Lalic, Gojko
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supporting information
p. 12464 - 12469
(2019/08/20)
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- AUTOTAXIN INHIBITORS COMPRISING A HETEROAROMATIC RING-BENZYL-AMIDE-CYCLE CORE
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The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.
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Page/Page column 303
(2015/02/02)
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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 Formula (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
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Paragraph 633; 634
(2015/11/02)
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- Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands
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5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2, 3-dimethoxybenzamide 1 is a potent and selective σ2 receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ1/σ2 binding affinity and selectivity. Compounds with a rigid piperidine spacer gave Ki values for the σ2 receptor between 8.7-845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ2Ki values of 4.4-133 nM whereas varying the length and flexibility of the carbon spaces gave σ2Ki values 0.88-15.0 nM, some of the most active, selective σ2 ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.
- Ashford, Mark E.,Nguyen, Vu H.,Greguric, Ivan,Pham, Tien Q.,Keller, Paul A.,Katsifis, Andrew
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p. 783 - 794
(2014/01/23)
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- PROCESS FOR THE PREPARATION OF IODIDES
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This invention is directed to a process for the preparation of high yield alkyl or aryl iodide from its corresponding carboxylic acid using N-iodo amides.
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Page/Page column 30
(2012/01/05)
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- Metal-free efficient, general and facile iododecarboxylation method with biodegradable co-products
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The development of a novel, efficient and robust method for the general conversion of aliphatic and aromatic carboxylic acids to organic iodides without the use of heavy metals or strong oxidizing agents is reported. Commercially available N-iodoamides were used for both initiation and halogen donation under irradiative conditions. Isolation of the product is extremely simple and the major co-product is removed as a water-soluble biodegradable material. Copyright
- Kulbitski, Kseniya,Nisnevich, Gennady,Gandelman, Mark
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supporting information; experimental part
p. 1438 - 1442
(2011/07/30)
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- BENZISOXAZOLE COMPOUND
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Disclosed is a compound represented by the general formula (I) or a salt thereof: wherein any one of R1, R2 and R3 represents a group represented by the formula: -(CH2)m-NR11R12 (wherein m is 1 or 2; and R11 and R12 independently represent a hydrogen atom or a C1-6 alkyl group or may, together with a nitrogen atom to which R11 and R12 are bound, form a 4- or 5-membered cyclic group); the remaining two or R1, R2 and R3 independently represent a group represented by the formula: -(O)n-R21 (wherein n is 0 or 1; and R21 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or the like); and R4 represents a C1-6 alkyl group which may have a substituent or the like.
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(2009/02/10)
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- THIAZOLE AND OXAZOLE KINASE INHIBITORS
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The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 151
(2009/07/17)
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- Potent, plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: Structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation
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New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT) and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial enzyme with IC50 values down to 1 nM, and that block the growth of P. falciparum in infected whole cells (erythrocytes) with ED50 values down to 55 nM. The structure-activity data for these second generation, ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of mammalian PFT and the homology model of the malarial enzyme.
- Fletcher, Steven,Cummings, Christopher G.,Rivas, Kasey,Katt, William P.,Hornéy, Carrie,Buckner, Frederick S.,Chakrabarti, Debopam,Sebti, Sa?d M.,Gelb, Michael H.,Van Voorhis, Wesley C.,Hamilton, Andrew D.
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experimental part
p. 5176 - 5197
(2009/07/01)
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- REGIOSELECTIVE PROCESS FOR PREPARING BENZIMIDAZOLE THIOPHENES
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The present invention provides a process for preparing benzimidazole thiophene compounds of formula I. Intermediates used in the process are also claimed.
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Page/Page column 231-232
(2010/11/26)
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- ARYL- AND HETEROARYLPIPERIDINECARBOXYLATE-DERIVATIVES METHODS FOR THEIR PREPARATION AND USE THEREOF AS FATTY ACID AMIDO HYDROLASE ENZYME INHIBITORS
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The present invention comprises compounds corresponding to the general formula (I): in which m, n=1 to 3 and m+n=2 to 5; p=1 to 7; A=single bond or X, Y and/or Z; X=optionally substituted methylene; Y=C2-alkenylene, which is optionally substitu
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(2010/11/25)
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- Solid-phase synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors
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A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered.
- Sutton, James C.,Bolton, Scott A.,Davis, Malcolm E.,Hartl, Karen S.,Jacobson, Bruce,Mathur, Arvind,Ogletree, Martin L.,Slusarchyk, William A.,Zahler, Robert,Seiler, Steven M.,Bisacchi, Gregory S.
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p. 2233 - 2239
(2007/10/03)
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- SUBSTITUTED PIPERAZINES, (1,4) DIASZEPINES, AND 2,5-DIAZABICYCLO (2.2.1) HEPTANES AS HISTAMINE H1 AND/OR H3 ANTAGONISTS OR HISTAMINE H3 REVERSE ANTAGONISTS
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The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer's disease.
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- Bradykin B1receptor antagonists
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Bradykinin B1-receptor antagonists of formula are disclosed. The compounds are useful for treating diseases associated with inappropriate bradykinin receptor activity, such as diabetic vasculopathy, inflammation, pain, hyperalgesia, asthma, rhinitis, septic shock, atherosclerosis and multiple sclerosis. Pyrimidines, triazines, and anilines in which Q is imidazolyl or pyrrolyl are particularly preferred.
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- 4-alkyl piperidinyl pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula I: (wherein R1, R2, R3, R4c, R4d, and R4f are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula 1: (wherein R1, R2, R3, R4, R5, R6and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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- Tartronic acids, their acetalic ethers and O-esters
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Tartronic acid acetalic ethers and esters of the general formula: STR1 are provided and are useful in treatment of bone dysmetabolism. As examples, Ra and Rb may be hydrogen, B is a C2 -C12 acyl group, R is phenyl and n is 0-12.
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- METHODS OF USING PIPERIDYL-BENZISOXAZOLE AND BENISOTHIAZOLE DERIVATIVES AS CHOLINESTERASE INHIBITORS
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Disclosed herein are compounds of the formula wherein R1 R2, R7, R8, X, Y, M and L are defined as below The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease
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- Fibrinogen receptor antagonists for inhibiting aggregation of blood platelets
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Fibrinogen receptor antagonists of the formula: STR1 are disclosed for use in inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
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- Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase
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A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3- methyl-1,2-benzisoxazoles with an iodo piperidine derivative as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl- over butyrylcholinesterase, in excess of 3 orders of magnitude. N-acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.
- Villalobos,Blake,Biggers,Butler,Chapin,Chen,Ives,Jones,Liston,Nagel,Nason,Nielsen,Shalaby,White
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p. 2721 - 2734
(2007/10/02)
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