- Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS)
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Abstract Human H-PGDS has shown promise as a potential target for anti-allergic and anti-inflammatory drugs. Here we describe the discovery of a novel class of indole inhibitors, identified through focused screening of 42,000 compounds and evaluated using a series of hit validation assays that included fluorescence polarization binding, 1D NMR, ITC and chromogenic enzymatic assays. Compounds with low nanomolar potency, favorable physico-chemical properties and inhibitory activity in human mast cells have been identified. In addition, our studies suggest that the active site of hH-PGDS can accommodate larger structural diversity than previously thought, such as the introduction of polar groups in the inner part of the binding pocket.
- Edfeldt, Fredrik,Even?s, Johan,Lepist?, Matti,Ward, Alison,Petersen, Jens,Wissler, Lisa,Rohman, Mattias,Sivars, Ulf,Svensson, Karin,Perry, Matthew,Feierberg, Isabella,Zhou, Xiao-Hong,Hansson, Thomas,Narjes, Frank
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p. 2496 - 2500
(2015/06/02)
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- METALLO-OXIDOREDUCTASE INHIBITORS USING METAL BINDING MOIETIES IN COMBINATION WITH TARGETING MOIETIES
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The presently disclosed subject matter is directed to metallo-oxidoreductase inhibitors having metal binding moities linked to a targeting moiety through a linking group or a direct bond, methods for screening for metallo-oxidoreductase inhibitors, and methods of treating an oxidoreductase related disorder by administering a metallo- oxidoreductase inhibitor to a subject in need of treatment thereof.
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Page/Page column 148
(2008/12/05)
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- studies on anti-helicobacter pylori agents. Part 2: New cephem derivatives
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The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of cephem derivatives are described. Introduction of thio-heterocyclic groups containing N- and S-atoms to the 3-position and phenyl or thienyl acetamido groups to the 7-position of the cephem nucleus dramatically improved the activity. From this series of derivatives, compound 13i was found to have extremely potent in vitro anti-H. pylori activity, superior therapeutic efficacy compared to AMPC and CAM, no cross-resistance between CAM or MNZ and low potential for causing diarrhea due to instability to β-lactamase. Copyright (C) 2000 Elsevier Science Ltd.
- Yoshida, Yoshiki,Matsuda, Keiji,Sasaki, Hiroshi,Matsumoto, Yoshimi,Matsumoto, Satoru,Tawara, Shuichi,Takasugi, Hisashi
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p. 2317 - 2335
(2007/10/03)
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- Structure-activity relationship within a series of pyrazolidinone antibacterial agents. 2. Effect of side-chain modification on in vitro activity and pharmacokinetic parameters
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The structure-activity relationship among a series of novel pyrazolidinone antibacterial agents is described. Specifically, the effect of modification of the side chain attached to the nitrogen at C-7 was explored in an attempt to improve the potency and spectrum of activity. This approach was successful in identifying several compounds having good in vitro profiles. These top candidates were then evaluated for their activity in vivo, and their pharmacokinetic behavior in various animal models was explored. This information proved critical for the identification of candidates for clinical evaluation.
- Ternansky,Draheim,Pike,Counter,Eudaly,Kasher
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p. 3224 - 3229
(2007/10/02)
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- 1-Oxacephalosporins: Enhancement of β-Lactam Reactivity and Antibacterial Activity
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The effect of replacement of sulfur in the cephem nucleus by oxygen upon the β-lactamase stability, infrared carbonyl frequency of the β-lactam ring, and antibacterial activity was investigated.The replacement reduced the stability of β-lactam compounds t
- Murakami, Kazuhisa,Takasuka, Mamoru,Motokawa, Kiyoshi,Yoshida, Tadashi
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- Δ2,3 -1,4-MORPHOLINE-2-CARBOXYLIC ACIDS AND DERIVATIVES THEREOF USEFUL IN PREPARATION OF ANTIBACTERIA AGENTS
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There is described novel substituted Δ2,3 -1, 4-morpholine-2-carboxylic acids possessing a fused β-lactam ring in the 1,6-position and carrying a substituent cis to carbon 5 in the 7-position of the fused ring system represented by the general formula STR1 wherein Q is hydrogen or alkyl and X is amino. Also included in the invention are compounds of the above formula in which the carboxyl group at the 2-position is protected as by an easily cleavable ester group and salts of both the free acids and carboxyl-protected compounds. The compounds and their physiologically hydrolyzed esters and pharmaceutically acceptable salts are useful as intermediates in the preparation of antibacterial agents.
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