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
  • 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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