- Substituted benzimidazoles as modulators of Ras signaling
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Benzimidazole compounds that increase the rate of SOS-mediated nucleotide exchange on Ras by binding to a functionally relevant, chemically tractable pocket on the SOS protein, as part of the Ras:SOS:Ras complex.
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Page/Page column 121-122
(2019/12/25)
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- IMPROVED PROCESSES FOR PREPARATION OF BILASTINE USING NOVEL INTERMEDIATES
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Provided herein are improved, commercially viable and industrially advantageous processes for the preparation of Bilastine or a pharmaceutically acceptable salt thereof using novel intermediates, in high yield and purity.
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Page/Page column 15; 16
(2018/03/25)
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- Discovery of Novel 2-(piperidin-4-yl)-1H-benzo[d]imidazole Derivatives as Potential Anti-Inflammatory Agents
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A novel 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 5 with good anti-inflammatory activity was identified from our in-house library. Based on hit compound 5, two series of 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 6a-g and 7a-h were designed and synthesized as novel anti-inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF-α production in LPS-stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC50 = 0.86 μm) and TNF-α (IC50 = 1.87 μm) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti-inflammatory activity than ibuprofen did on xylene-induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF-κB in LPS-stimulated RAW 264.7 macrophages.
- Li, Qing,Hu, Qinghua,Wang, Xinning,Zong, Yang,Zhao, Leilei,Xing, Junhao,Zhou, Jinpei,Zhang, Huibin
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p. 509 - 516
(2015/03/30)
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- Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the PDEδ prenyl binding site
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K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras-PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras.
- Zimmermann, Gunther,Schultz-Fademrecht, Carsten,Küchler, Philipp,Murarka, Sandip,Ismail, Shehab,Triola, Gemma,Nussbaumer, Peter,Wittinghofer, Alfred,Waldmann, Herbert
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supporting information
p. 5435 - 5448
(2014/07/08)
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- DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS
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Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.
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Page/Page column 7; 87-90
(2011/12/02)
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- Modifications to five-substituted 3,3-diethyl-4,5-dihydro-2(3H)- Furanones en route to novel muscarinic receptor ligands
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Lead lactone-based ligands with modest affinity for muscarinic receptors were modified based on structure- activity relationship data in the literature to provide a new series of 5-substituted 4,5-dihydro-2(3H)-furanones. The modifications included the addition of various nitrogencontaining heterocycles attached to substituted and unsubstituted aromatic rings. The target compounds were synthesized in modest yields and evaluated in preliminary muscarinic binding assays. A lactone-based ligand containing a diphenylmethylpiperazine moiety was identified as a nonselective muscarinic ligand with IC50 of 340 nM. The design of future ligands will be based, in part, on structure-activity data reported herein. Springer Science+Business Media, LLC 2011.
- Bhandare, Richie R.,Canney, Daniel J.
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scheme or table
p. 558 - 565
(2012/04/17)
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- BRIDGED TETRAHYDRONAPHTHALENE DERIVATIVES
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The invention relates to compounds of formula (I) wherein R1, R2, R3, R4, A, B, W and n are as defined in the description, and to pharmaceutically acceptable salts of such compounds. These compounds are useful as calcium channel blockers.
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Page/Page column 30
(2010/05/13)
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- SEROTONIN 5-HT2B RECEPTOR INHIBITORS
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Disclosed are Serotonin 5-HT2B receptor inhibitors of the formula I. Also disclosed are methods of making and methods of using these compounds
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Page/Page column 41-42
(2010/08/04)
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- A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties
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We have been exploring the potential of 5-HT2B antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonis
- Moss, Neil,Choi, Younggi,Cogan, Derek,Flegg, Adam,Kahrs, Andreas,Loke, Pui,Meyn, Orietta,Nagaraja, Raj,Napier, Spencer,Parker, Ashley,Thomas Peterson,Ramsden, Philip,Sarko, Christopher,Skow, Donna,Tomlinson, Josh,Tye, Heather,Whitaker, Mark
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scheme or table
p. 2206 - 2210
(2009/12/07)
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- QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
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The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.
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Page/Page column 90
(2008/12/06)
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- Method for treating allergies using substituted pyrazoles
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A method for treating an allergic condition, including an atopic allergic condition, using substituted pyrazoles.
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- Synthesis and evaluation of novel bacterial rRNA-binding benzimidazoles by mass spectrometry
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A series of novel benzimidazoles were efficiently synthesized using both solution- and solid-phase chemistry. These compounds were found to bind to the bacterial 16S ribosomal RNA A-site with micromolar affinities using unique mass spectrometry-based assays.
- He, Yun,Yang, Jun,Wu, Baogen,Robinson, Dale,Sprankle, Kelly,Kung, Pei-Pei,Lowery, Kristin,Mohan,Hofstadler, Steve,Swayze, Eric E.,Griffey, Rich
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p. 695 - 699
(2007/10/03)
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- PROLINE DERIVATIVES AND USE THEREOF AS DRUGS
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The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.
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- Sulfonamide derivatives as 5-HT7 receptor antagonists
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The invention relates to novel sulfonamide compounds having 5-HT7receptor antagonist activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders. wherein: Q is phenyl or thienyl; R1is halogen, hydroxy, C1-6alkyl, CF3, OCF3or C1-6alkoxy; m is 0, 1, 2 or 3; R2is C1-4alkyl; X is carbon or CH, is a single bond when X is nitrogen or CH or is a double bond when X is carbon, D is a single bond, C═O, O or CH2subject to the proviso that when X is nitrogen then D is not oxygen; P is a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzofused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; R3is C1-6alkyl optionally substituted by NR4R5, aryl, arylC1-6alkyl, C1 6alkoxy, C1-6alkylthio, cyano, hydroxy, nitro, halogen, CF3, C2F5, NR4R5, CONR4R5, NR4COR5, S(O)pNR4R5, CHO, OCF3, SCF3, CH2OR6, CO2R6or COR6where p is 0, 1 or 2 and R4, R5and R6are independently hydrogen, C1-6alkyl, aryl or arylC1-6alkyl; n is 0, 1, 2 or 3.
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Page column 7,8
(2010/11/30)
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- Synthesis and structure-activity relationship of new piperidinyl and piperazinyl derivatives as antiallergics
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A series of piperazinebenzothiazoles 3-5, piperazinebenzimidazoles 6-12, piperidinobenzothiazoles 14-45, piperidinobenzoxazoles 46-52 and piperidinobenzimidazoles 53-129 has been synthesized and their antiallergic activity evaluated by means of the passive cutaneous anaphylaxis (PCA) assay. Structure-activity relationships are discussed and related to classical antihistaminics. Piperidino derivatives with an aryl group linked to the nitrogen atom by an ethyl chain are the most active compounds, with ID50 1 mg/kg po. Some of these compounds are more potent antiallergics than astemizole and terfenadine.
- Orjales,Bordell,Rubio
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p. 707 - 718
(2007/10/02)
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- Synthesis of Some Benzimidazole-, Pyridine- and Imidazole-Derived Chelating Agents
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Procedures are described for the preparation of various bidentate and potentially tridentate chelating agents.These incorporate pyridyl, benzimidazole, imidazole or phenolic moieties.Phillips condensations of carboxylic acids with o-phenylenediamines were carried out in 4 M hydrochloric acid.Syntheses are reported for 2,6-bis(N'-methylimidazol-2'-ylthiomethyl)pyridine, 2,6-bis(benzimidazol-2'-ylthiomethyl)pyridine, 2-(4'-piperidyl)benzimidazole, 2-(3'-piperidyl)benzimidazole, 2-(3-N'-methylpiperidyl)benzimidazole, 2-(3-N'-methylpiperidyl)-N-methylbenzimidazole, 2-(2'-hydroxybenzyl)benzimidazole and 2-(2'-hydroxybenzyl)-N-methylbenzimidazole.The compounds were characterized where appropriate by their mass, uv, and 1H-nmr spectra. 2-(2'-Hydroxybenzyl)benzimidazole hydrochloride acts as a gelling agent in aqueous solution.
- Wahlgren, Curtis G.,Addison, Anthony W.
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p. 541 - 543
(2007/10/02)
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