Journal of Medicinal Chemistry p. 8136 - 8154 (2018)
Update date:2022-08-15
Topics:
Baqi, Younis
Pillaiyar, Thanigaimalai
Abdelrahman, Aliaa
Kaufmann, Olesja
Alshaibani, Samer
Rafehi, Muhammad
Ghasimi, Saman
Akkari, Rhalid
Ritter, Kirsten
Simon, Katharina
Spinrath, Andreas
Kostenis, Evi
Zhao, Qiang
K?se, Meryem
Namasivayam, Vigneshwaran
Müller, Christa E.
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.
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