New ligands of the ghrelin receptor based on the 1,2,4-triazole scaffold by introduction of a second chiral center

  • Bioorg Med Chem Lett. 2016 May 15;26(10):2408-2412. doi: 10.1016/j.bmcl.2016.04.003.
Mathieu Maingot  1 ,  Anne-Laure Blayo  1 ,  Séverine Denoyelle  1 ,  Céline M'Kadmi  1 ,  Marjorie Damian  1 ,  Sophie Mary  1 ,  Didier Gagne  1 ,  Pierre Sanchez  1 ,  Babette Aicher  2 ,  Peter Schmidt  2 ,  Gilbert Müller  2 ,  Michael Teifel  2 ,  Eckhard Günther  2 ,  Jacky Marie  1 ,  Jean-Louis Banères  1 ,  Jean Martinez  1 ,  Jean-Alain Fehrentz  3
Affiliations
  • 1. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, ENSCM, Université de Montpellier, BP 14491, Faculté de Pharmacie, bât. E, 3(ème) étage, 15 avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
  • 2. Æterna Zentaris GmbH, Weismuellerstrasse 50, 60314 Frankfurt am Main, Germany.
  • 3. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, ENSCM, Université de Montpellier, BP 14491, Faculté de Pharmacie, bât. E, 3(ème) étage, 15 avenue Charles Flahault, 34093 Montpellier Cedex 5, France. Electronic address: [email protected].
PMID: 27072910 DOI: 10.1016/j.bmcl.2016.04.003
Abstract

Introducing a second chiral center on our previously described 1,2,4-triazole, allowed us to increase diversity and elongate the 'C-terminal part' of the molecule. Therefore, we were able to explore mimics of the substance P analogs described as inverse agonists. Some compounds presented affinities in the nanomolar range and potent biological activities, while one exhibited a partial inverse agonist behavior similar to a Substance P analog.

Keywords
1,2,4-Triazole scaffold; Antagonist; Chirality; Ghrelin receptor (GHS-R1a); Inverse agonist; Structural modulation.