- Synthesis and Stereochemical Assignment of Conioidine A: DNA- And HSA-Binding Studies of the Four Diastereomers
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Conioidine A (1), isolated in 1993 with unknown relative and absolute configuration, was suggested to be a DNA-binding compound by an indirect technique. Four stereoisomers of conioidine A have been synthesized from d- and l-proline, and the natural product has been identified as possessing (4R,6R) absolute configuration. Binding of the conioidine diastereomers to calf thymus DNA (CT DNA) and human serum albumin (HSA) has been investigated by fluorescence spectroscopy and isothermal titration calorimetry (ITC). All stereoisomers display at least an order of magnitude weaker binding to DNA than the control compound netropsin; however, a strong association with HSA was observed for the (4R,6S) stereoisomer.
- Shaktah, Ryan,Vardanyan, Laura,David, Elroma,Aleman, Alexis,Orr, Dupre,Shaktah, Lawrence A.,Tamae, Daniel,Minehan, Thomas
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supporting information
p. 3191 - 3198
(2020/11/03)
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- Pyrrolidine-Oxadiazolone Conjugates as Organocatalysts in Asymmetric Michael Reaction
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Pyrrolidine-oxadiazolone based organocatalysts are envisaged, synthesized, and utilized for asymmetric Michael reactions. Results of the investigations suggest that some of the catalysts are indeed efficient for stereoselective 1,4-conjugated Michael additions (dr: >97:3, ee up to 99%) in high chemical yields (up to 97%) often in short reaction time. As an extension, one enantiopure Michael adduct has been utilized to synthesize optically active octahydroindole.
- Mahato, Chandan K.,Mukherjee, Sayan,Kundu, Mrinalkanti,Pramanik, Animesh
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p. 1053 - 1063
(2019/01/14)
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- AMINOPYRIDINE COMPOUNDS AND METHODS FOR THE PREPARATION AND USE THEREOF
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The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis, including its proteases arginine gingipain A/B (Rgp), and their use for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimer's disease. In certain embodiments, the invention provides compounds according to Formula I and Formula III, as described herein, and pharmaceutically acceptable salts thereof.
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Paragraph 0283
(2018/12/02)
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- FUMAGILLOL HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING SAME
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Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Paragraph 00208
(2017/03/08)
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- Solvent free, fast and asymmetric Michael additions of ketones to nitroolefins using chiral pyrrolidine–pyridone conjugate bases as organocatalysts
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New chiral organocatalysts are envisaged based on a pyrrolidine–pyridone conjugate and synthesized from commercially available proline employing standard protocols. These catalysts were found to be useful for asymmetric Michael additions of ketones to nitroolefins to afford the desired products in very good yields (up to 98%) with excellent diastereo- and enantioselectivities (>97:3 syn/anti and up to 98% ee) in very short reaction time compared with the existing reports.
- Mahato, Chandan K.,Kundu, Mrinalkanti,Pramanik, Animesh
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p. 511 - 515
(2017/04/28)
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- Enantioselective Synthesis of 6,6-Disubstituted Pentafulvenes Containing a Chiral Pendant Hydroxy Group
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Simple enantioselective synthesis of 6,6-disubstituted pentafulvenes bearing chiral pendant hydroxy groups are attained by cascade reactivity using commercially available proline-based organocatalysts. Condensation of cyclopentadiene with the acetyl function of a 1,2-formylacetophenone, followed by cyclization of a resulting fulvene-stabilized carbanion with the formyl group, generates bicyclic chiral alcohols with initial er values up to 94:6. Exceptional enantio-enrichment of the resultant alcohols results upon crystallization—even near racemic samples spontaneously de-racemize. This enables new families of substituted cyclopentadienes that are both enantiomerically and diastereomerically pure to be rapidly attained.
- Nouch, Ryan,Cini, Melchior,Magre, Marc,Abid, Mohammed,Diéguez, Montserrat,Pàmies, Oscar,Woodward, Simon,Lewis, William
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supporting information
p. 17195 - 17198
(2017/11/27)
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- 5-AMINO-4-CARBAMOYL-PYRAZOLE COMPOUNDS AS SELECTIVE AND IRREVERSIBLE T790M OVER WT-EGFR KINASE INHIBITORS AND USE THEREOF????
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Disclosed are compounds of Formula (I), pharmaceutical compositions comprising the same, processes for the preparation thereof, and the use thereof.
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Paragraph 0087
(2016/03/13)
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- METHODS OF TREATING LIVER DISEASES
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The invention provides tricyclic compounds and their use in treating liver disorders, such as non-alcoholic steatohepatitis and related disorders (e.g., fibrosis). The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Paragraph 00411; 00416
(2014/05/24)
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- PARTIALLY SATURATED TRICYCLIC COMPOUNDS AND METHODS OF MAKING AND USING SAME
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The invention provides tricyclic compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making various tricyclic compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Page/Page column 182
(2012/12/13)
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- Discovery of 4-[(2S)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl] butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis
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Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA4H) as a key target for the treatment of cardiovascular disease. We combined fragmentbased crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA4H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA4H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (Kd=26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.
- Sandanayaka, Vincent,Mamat, Bjorn,Mishra, Rama K.,Winger, Jennifer,Krohn, Michael,Zhou, Li-Ming,Keyvan, Monica,Enache, Livia,Sullins, David,Onua, Emmanuel,Zhang, Jun,Halldorsdottir, Gudrun,Sigthorsdottir, Heida,Thorlaksdottir, Audur,Sigthorsson, Gudmundur,Thorsteinnsdottir, Margret,Davies, Douglas R.,Stewart, Lance J.,Zembower, David E.,Andresson, Thorkell,Kiselyov, Alex S.,Singh, Jasbir,Gurney, Mark E.
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experimental part
p. 573 - 585
(2010/07/09)
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- 5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)-A potent FLAP inhibitor
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A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model.
- Stock, Nicholas,Baccei, Christopher,Bain, Gretchen,Broadhead, Alex,Chapman, Charles,Darlington, Janice,King, Christopher,Lee, Catherine,Li, Yiwei,Lorrain, Daniel S.,Prodanovich, Pat,Rong, Haojing,Santini, Angelina,Zunic, Jasmine,Evans, Jilly F.,Hutchinson, John H.,Prasit, Peppi
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scheme or table
p. 213 - 217
(2010/04/24)
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- NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS
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Disclosed herein are compounds of formula (I) wherein R1, R2, R3, R25a, R26a, X, and n are as defined in the specification. Pharmaceutical compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and pharmaceutical compositions are also described
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Page/Page column 33
(2009/10/06)
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- SUBSTITUTED BENZHYDRYLETHERS
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Disclosed herein are substituted benzhydrylethers of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of their use thereof.
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Page/Page column 33
(2009/08/18)
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- Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography
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We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facili
- Davies, Douglas R.,Mamat, Bjorn,Magnusson, Olafur T.,Christensen, Jeff,Haraldsson, Magnus H.,Mishra, Rama,Pease, Brian,Hansen, Erik,Singh, Jasbir,Zembower, David,Kim, Hidong,Kiselyov, Alex S.,Burgin, Alex B.,Gurney, Mark E.,Stewart, Lance J.
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experimental part
p. 4694 - 4715
(2010/03/02)
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- BIARYL SUBSTITUTED HETEROCYCLE INHIBITORS OF LTA4H FOR TREATING INFLAMMATION
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The present invention relates to a chemical genus of biaryl substituted heterocycle inhibitors of LTA4H (leukotriene A4 hydrolase) useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders. The compounds have general formula Ψ: An example is
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Page/Page column 20-21; 47
(2008/06/13)
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- Process for preparing 2-methylpyrrolidine and specific enantiomers thereof
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The invention relates to a process for preparing 2-methylpyrrolidine and, more particularly, specific enantiomers of 2-methylpyrrolidine. Novel intermediates also are described.
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- Process for preparing 2-methylpyrrolidine and specific enantiomers thereof
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The invention relates to a process for preparing 2-methylpyrrolidine and, more particularly, specific enantiomers of 2-methylpyrrolidine. Novel intermediates also are described.
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- HETEROCYCLIC KINASE INHIBITORS
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Compounds having the formula (I) are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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- Endomorphin-1 analogues containing β-proline are μ-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance
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In this paper we describe the synthesis and affinity toward the μ-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH2 (1), by substituting each amino acid in turn with its homologue. The ability to bind μ -opioid receptors depends on the β-amino acid, and in particular 4, which contains β-L-Pro, has a KI, in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the μ-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as μ-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential μ-opioid receptor agonists.
- Cardillo, Giuliana,Gentilucci, Luca,Qasem, Ahmed R.,Sgarzi, Fabio,Spampinato, Santi
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p. 2571 - 2578
(2007/10/03)
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- ANTITHROMBOTIC AGENTS
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Compounds of formula (I): Are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisa
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- Antithrombotic agents
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Compounds of formula (I) : are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilis
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- N-Acyl-2-substituted-1,3-thiazolidines, a New Class of Non-narcotic Antitussive Agents: Studies Leading to the Discovery of Ethyl 2--β-oxothiazolidine-3-propanoate
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The synthesis of a novel class of antitussive agents is described.The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation.Ethyl 2--β-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan.The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents.The serendipitous discovery of the role played by the thiazolidine moiety in the determining the antitussive effect promoted extensive investigations on these structures.This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2--3--1,3-thiazolidine (18a) as an interesting lead compound.The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives.The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety.Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity.This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series.Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.
- Gandolfi, Carmelo A.,Domenico, Roberto Di,Spinelli, Silvano,Gallico, Licia,Fiocchi, Luigi,et al.
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p. 508 - 525
(2007/10/02)
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