A paradigm for drug discovery employing encoded combinatorial libraries.

DOI Web Site 被引用文献3件
  • J J Burbaum
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • M H Ohlmeyer
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • J C Reader
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • I Henderson
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • L W Dillard
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • G Li
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • T L Randle
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • N H Sigal
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • D Chelsky
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
  • J J Baldwin
    Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.

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<jats:p>Very large combinatorial libraries of small molecules on solid supports can now be synthesized and each library element can be identified after synthesis by using chemical tags. These tag-encoded libraries are potentially useful in drug discovery, and, to test this utility directly, we have targeted carbonic anhydrase (carbonate dehydratase; carbonate hydro-lyase, EC 4.2.1.1) as a model. Two libraries consisting of a total of 7870 members were synthesized, and structure-activity relationships based on the structures predicted by the tags were derived. Subsequently, an active representative of each library was resynthesized (2-[N-(4-sulfamoylbenzoyl)-4'-aminocyclohexanespiro]-4-oxo-7 -hydroxy- 2,3-dihydrobenzopyran and [N-(4-sulfamoylbenzoyl)-L-leucyl]piperidine-3-carboxylic acid) and these compounds were shown to have nanomolar dissociation constants (15 and 4 nM, respectively). In addition, a focused sublibrary of 217 sulfamoylbenzamides was synthesized and revealed a clear, testable structure-activity relationship describing isozyme-selective carbonic anhydrase inhibitors.</jats:p>

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