Prev. Article Next Article Table of Contents

Article

Fragment Based Design of New H₄ Receptor−Ligands with Anti-inflammatory Properties in Vivo

Supporting Info

Rogier A. Smits^†, Herman D. Lim^†, Agnes Hanzer^†, Obbe P. Zuiderveld^†, Elena Guaita^‡, Maristella Adami^‡, Gabriella Coruzzi^‡, Rob Leurs^† and Iwan J. P. de Esch*^†

Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, Department of Human Anatomy, Pharmacology, and Forensic Medicine, Section of Pharmacology, University of Parma, via Volturno 39, 43100 Parma, Italy

J. Med. Chem., 2008, 51 (8), pp 2457–2467

DOI: 10.1021/jm7014217

Publication Date (Web): March 22, 2008

†

Leiden/Amsterdam Center for Drug Research (LACDR), Vrije Universiteit Amsterdam.

‡

Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma.

* To whom correspondence should be addressed. Phone: +31(0)205987841 . Fax: +31(0)205987610. E-mail: ideesch@few.vu.nl.

Abstract

Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H₄ receptor (H₄R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline (3) was identified as a new lead structure for H₄R ligands. Exploration of the structure−activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H₄R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Tools

SciFinder Links

History

Published In Issue April 24, 2008
Article ASAPMarch 22, 2008
Received: November 11, 2007

Recommend & Share

Related Content

Recent Developments in Fragment-Based Drug DiscoveryJournal of Medicinal Chemistry
- Recent Developments in Fragment-Based Drug Discovery
  Miles Congreve, Gianni Chessari, Dominic Tisi and Andrew J. Woodhead
  Journal of Medicinal Chemistry 2008 51 (13), pp 3661–3680
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H₄ Receptor LigandsJournal of Medicinal Chemistry
- Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H₄ Receptor Ligands
  Robert J. Altenbach, Ronald M. Adair, Brian M. Bettencourt, Lawrence A. Black, Shannon R. Fix-Stenzel, Sujatha M. Gopalakrishnan, Gin C. Hsieh, Huaqing Liu, Kennan C. Marsh, Michael J. McPherson, Ivan Milicic, Thomas R. Miller, Timothy A. Vortherms, Usha Warrior, Jill M. Wetter, Neil Wishart, David G. Witte, Prisca Honore, Timothy A. Esbenshade, Arthur A. Hancock, Jorge D. Brioni and Marlon D. Cowart
  Journal of Medicinal Chemistry 2008 51 (20), pp 6571–6580
  Abstract: A series of 2-aminopyrimidines was synthesized as ligands of the histamine H₄ receptor (H₄R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4-...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄ Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation ModelsJournal of Medicinal Chemistry
- Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄ Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models
  Marlon D. Cowart, Robert J. Altenbach, Huaqing Liu, Gin C. Hsieh, Irene Drizin, Ivan Milicic, Thomas R. Miller, David G. Witte, Neil Wishart, Shannon R. Fix-Stenzel, Michael J. McPherson, Ronald M. Adair, Jill M. Wetter, Brian M. Bettencourt, Kennan C. Marsh, James P. Sullivan, Prisca Honore, Timothy A. Esbenshade and Jorge D. Brioni
  Journal of Medicinal Chemistry 2008 51 (20), pp 6547–6557
  Abstract: A new structural class of histamine H₄ receptor antagonists (6−14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H₄ antagonism across multiple species, good CNS penetration, ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF

Article

Fragment Based Design of New H₄ Receptor−Ligands with Anti-inflammatory Properties in Vivo