231
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Discovery of 1,2,4-Triazine Derivatives as Adenosine A 2A Antagonists using Structure Based Drug Design

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A 2A receptor. The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound 4k are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson’s disease.

          Related collections

          Most cited references8

          • Record: found
          • Abstract: not found
          • Article: not found

          Ligand efficiency: a useful metric for lead selection.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine.

            Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized adenosine A(2A) receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A(2A) selective inverse agonist ZM241385. The receptor is crystallized in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features that define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions that interact with signal transduction proteins. Copyright © 2011 Elsevier Ltd. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Meta halogenation of 1,3-disubstituted arenes via iridium-catalyzed arene borylation.

                Bookmark

                Author and article information

                Journal
                J Med Chem
                J. Med. Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                05 January 2012
                08 March 2012
                : 55
                : 5
                : 1898-1903
                Affiliations
                [1]Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
                Author notes
                [* ]Phone +44 (0)1707 358638. E-mail: miles.congreve@ 123456heptares.com .
                Article
                10.1021/jm201376w
                3308197
                22220592
                dd53d3ee-c4be-44b6-babc-96501e67b92d
                Copyright © 2012 American Chemical Society

                This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.

                History
                : 12 October 2011
                : 27 January 2012
                : 08 March 2012
                : 05 January 2012
                Categories
                Article
                Custom metadata
                jm201376w
                jm-2011-01376w

                Pharmaceutical chemistry
                Pharmaceutical chemistry

                Comments

                Comment on this article