- COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS AND POTENTIATION OF ANTIBIOTICS
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Compounds and methods for use to treat a bacterial infection caused by, for example, gram positive bacteria, gram negative bacteria, and/or mycobacteria are provided herein. Also provided herein are compounds and methods for use in potentiating the effect of an antibiotic in the treatment of a bacterial infection. Pharmaceutical compositions including the compounds as described herein are also provided.
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Page/Page column 97; 114
(2021/06/26)
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- CENTRALLY ACTIVE P38ALPHA INHIBITING COMPOUNDS
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Compounds that are inhibitors of p38alpha and centrally available are described.
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- Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type i 1/2 p38α MAP Kinase Inhibitors
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The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe N-acylhydrazone and selenophene residues as spine motifs, yielding metabolically stable inhibitors with high potency on enzymatic, NanoBRET, and whole blood assays, improved metabolic stability, and prolonged TRT.
- Pedreira, Júlia G. B.,Nahidino, Philipp,Kudolo, Mark,Pantsar, Tatu,Berger, Benedict-Tilman,Forster, Michael,Knapp, Stefan,Laufer, Stefan,Barreiro, Eliezer J.
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supporting information
p. 7347 - 7354
(2020/09/11)
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- AMIDINES AND AMIDINE ANALOGS FOR THE TREATMENT OF BACTERIAL INFECTIONS AND POTENTIATION ANTIBIOTICS
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Compounds and methods for the treatment of a bacterial infection or the potentiation of an antibiotic in treating a bacterial infection are described herein.
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Page/Page column 400
(2020/01/08)
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- HETEROCYCLIC COMPOUNDS AS INHIBITORS OF RAS AND METHODS OF USE THEREOF
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Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R", Q, W, X, Y, Z, n1, n2and '--" are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also disclosed.
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- Synthesis of isophthalates from methyl coumalate
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Methyl coumalate reacts with enol ethers to form stable adducts which can be converted into isophthalates in good to excellent yields. Alkyl vinyl ethers afford higher yields of isophthalates than enol silyl ethers. The adduct of the enol silyl ether of acetophenone with methyl coumalate reacted with PTSA to produce a styryl coumalate.
- Kraus, George A.,Wang, Shuai
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p. 56760 - 56763
(2017/12/27)
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- Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine
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We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.
- Walter, Niklas M.,Wentsch, Heike K.,Bührmann, Mike,Bauer, Silke M.,D?ring, Eva,Mayer-Wrangowski, Svenja,Sievers-Engler, Adrian,Willemsen-Seegers, Nicole,Zaman, Guido,Buijsman, Rogier,L?mmerhofer, Michael,Rauh, Daniel,Laufer, Stefan A.
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p. 8027 - 8054
(2017/10/18)
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- Upgrading malic acid to bio-based benzoates via a Diels-Alder-initiated sequence with the methyl coumalate platform
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The conversion of naturally-occurring malic acid to the 2-pyrone methyl coumalate was optimized using a variety of acid catalysts. Coupling methyl coumalate with electron-rich dienophiles in an inverse electron-demand Diels-Alder (IEDDA)/decarboxylation/elimination domino sequence resulted in an investigation of the scope and limitations of the methodology. The thermal, metal-free, and one-pot procedure allows regioselective access to diverse aromatic compounds including tricyclic, biphenyl, and pyridinyl systems for elaboration. A comparison with analogous pyrones demonstrates the striking efficacy of methyl coumalate as a versatile platform for the generation of biorenewable functionalized benzoates. This journal is
- Lee, Jennifer J.,Pollock Iii, Gerald R.,Mitchell, Donald,Kasuga, Lindsay,Kraus, George A.
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p. 45657 - 45664
(2015/02/19)
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- Cobalt-catalyzed methoxycarbonylation of substituted dichlorobenzenes as an example of a facile radical anion nucleophilic substitution in chloroarenes
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A thorough mechanistic study on cobalt-catalysed direct methoxycarbonylation reactions of chlorobenzenes in the presence of methyl oxirane on a wide range of substrates, including poly-and monochloro derivatives with multiple substituents, is reported. The results demonstrate that the reaction is potentially useful as it proceeds under very mild conditions (t = 62 °C, PCO = 1 bar) and converts aryl chlorides to far more valuable products (especially ortho-substituted benzoic acids and esters) in high yields. This transformation also offers another opportunity for the utilization of environmentally harmful polychlorinated benzenes and biphenyls (PCBs). This study is the first to discover an unexpected universal positive ortho-effect: the proximity of any substituent (including Me, Ph, and MeO groups and halogen atoms) to the reaction centre accelerates the methoxycarbonylation in chlorobenzenes. The effect of the ortho-substituents is discussed in detail and explained in terms of a radical anion reaction mechanism. The advantages of the methoxycarbonylation as a model for the mechanistic study of radical anion reactions are also illustrated.
- Khaibulova, Tatyana S.,Boyarskaya, Irina A.,Larionov, Evgeny,Boyarskiy, Vadim P.
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p. 5876 - 5897
(2014/06/10)
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- Dibenzosuberones as p38 mitogen-activated protein kinase inhibitors with low ATP competitiveness and outstanding whole blood activity
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p38α mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38α MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.
- Fischer, Stefan,Wentsch, Heike K.,Mayer-Wrangowski, Svenja C.,Zimmermann, Markus,Bauer, Silke M.,Storch, Kirsten,Niess, Raimund,Koeberle, Solveigh C.,Grütter, Christian,Boeckler, Frank M.,Rauh, Daniel,Laufer, Stefan A.
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p. 241 - 253
(2013/03/13)
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- NOVEL ISOINDOLINONE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST T-TYPE CALCIUM CHANNEL AND METHOD FOR PREPARATION THEREOF
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Disclosed are isoindolinone derivatives having inhibitory activity against T-type calcium channels, pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient
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Page/Page column 15
(2010/04/03)
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- NOVEL ISOINDOLINONE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST T-TYPE CALCIUM CHANNEL AND METHOD FOR PREPARATION THEREOF
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Disclosed are isoindolinone derivatives, represented by Chemical Formula 1, having inhibitory activity against T-type calcium channels, pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient. wherein R1?R6 are as defined in the specification.
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Page/Page column 6
(2010/02/16)
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- DIPEPTIDYL PEPTIDASE-IV INHIBITORS
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The present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.
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Page/Page column 87-88
(2008/06/13)
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- Methods of making 2,6-diaryl piperidine derivatives
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Methods for preparing 2,6-diaryl piperidine derivatives are described. More particularly, 2,6-diaryl piperidines having formula 1-4 are prepared by cyclocondensation of an aryl or heteroaryl aldehyde with 1,3-acetonedicarboxylic acid.
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- Compounds and methods for identifying activated platelets
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The invention is directed to a series of novel compounds, and their pharmaceutically acceptable salts, of the formula STR1 wherein R is C0-6 alkyl substituted with R5 or a mono or polycyclic aromatic or heteroaromatic system comprised of 5 or 6-membered aromatic or heteroaromatic rings that are either unsubstituted or substituted with one or more of R1 and R2 ; R1 and R2 are independently C1-6 alkyl, carboxyl, hydroxyl, azido, nitro, amino, C1-6 alkylamino, C1-6 dialkylamino, arylamino, aryl C1-6 alkylamino, hydroxysulfonyl or arylazo; aryl is a phenyl or naphthyl ring which is unsubstituted or substituted with one or more of R3 and R4 ; R3 and R4 are independently C1-6 alkyl, azido, nitro, amino, C1-6 dialkylamino or hydroxysulfonyl; R5 is STR2 provided that when R is an unsubstituted monocyclic ring, the monocyclic ring is not phenyl or pyridyl. Such compounds are useful as fluorescent probes for identifying antiplatelet agents which selectively bind to activated platelets.
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- Fibrinogen receptor antagonists
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Novel fibrinogen receptor antagonists of the formula: are provided in which the claimed compounds exhibit fibrinogen receptor antagonist activity, inhibit platelet aggregation and are therefore useful in modulating thrombus formation.
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- Nonpeptide GPIIB/IIIA inhibitors. 10. Centrally constrained alpha-sulfonamides are potent inhibitors of platelet aggregation
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Potency enhancing features of two series of fibrinogen receptor antagonists were combined to give analogs with improved potency and oral activity. Antagonists containing either alkyl or aryl sulfonamides and a central isoindolinone structural constraint demonstrate high affinity for both activated and unactivated platelet receptors.
- Egbertson,Hartman,Gould,Bednar,Bednar,Cook,Gaul,Holahan,Libby,Lynch Jr.,Lynch,Sitko,Stranieri,Vassallo
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p. 2519 - 2524
(2007/10/03)
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- Fibrinogen receptor antagonists
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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 wherein G is: STR2
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