2. Academic Validation
  3. 3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17

3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17

  • J Med Chem. 2018 Sep 27;61(18):8136-8154. doi: 10.1021/acs.jmedchem.7b01768.
Younis Baqi 1,  Thanigaimalai Pillaiyar 2,  Aliaa Abdelrahman 2,  Olesja Kaufmann 2,  Samer Alshaibani 2,  Muhammad Rafehi 2,  Saman Ghasimi 2,  Rhalid Akkari 2,  Kirsten Ritter 2,  Katharina Simon 3,  Andreas Spinrath 3,  Evi Kostenis 3,  Qiang Zhao 4,  Meryem Köse 2,  Vigneshwaran Namasivayam 2,  Christa E Müller 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science , Sultan Qaboos University , P.O. Box 36, 123 Muscat , Oman.
  • 2 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical Chemistry I , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany.
  • 3 Institute of Pharmaceutical Biology, Section Molecular-, Cellular-, and Pharmacobiology, University of Bonn , Nußallee 6 , 53115 Bonn , Germany.
  • 4 CAS Key Laboratory of Receptor Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Pudong , Shanghai 201203 , China.
PMID: 30048589 DOI: 10.1021/acs.jmedchem.7b01768
Abstract

The Orphan Receptor GPR17 may be a novel drug target for inflammatory diseases. 3-(2-Carboxyethyl)-4,6-dichloro-1 H-indole-2-carboxylic acid (MDL29,951, 1) was previously identified as a moderately potent GPR17 agonist. In the present study, we investigated the structure-activity relationships (SARs) of 1. Substitution of the indole 1-, 5-, or 7-position was detrimental. Only small substituents were tolerated in the 4-position while the 6-position accommodated large lipophilic residues. Among the most potent compounds were 3-(2-carboxyethyl)-1 H-indole-2-carboxylic acid derivatives containing the following substituents: 6-phenoxy (26, PSB-1737, EC50 270 nM), 4-fluoro-6-bromo (33, PSB-18422, EC50 27.9 nM), 4-fluoro-6-iodo (35, PSB-18484, EC50 32.1 nM), and 4-chloro-6-hexyloxy (43, PSB-1767, EC50 67.0 nM). (3-(2-Carboxyethyl)-6-hexyloxy-1 H-indole-2-carboxylic acid (39, PSB-17183, EC50 115 nM) behaved as a partial agonist. Selected potent compounds tested at human P2Y Receptor subtypes showed high selectivity for GPR17. Docking into a homology model of the human GPR17 and molecular dynamic simulation studies rationalized the observed SARs.

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