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

The
orphan receptor GPR17 may be a novel drug target for inflammatory
diseases. 3-(2-Carboxyethyl)-4,6-dichloro-1H-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)-1H-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-1H-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.