TY - JOUR
T1 - 3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives
T2 - Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17
AU - Baqi, Younis
AU - Pillaiyar, Thanigaimalai
AU - Abdelrahman, Aliaa
AU - Kaufmann, Olesja
AU - Alshaibani, Samer
AU - Rafehi, Muhammad
AU - Ghasimi, Saman
AU - Akkari, Rhalid
AU - Ritter, Kirsten
AU - Simon, Katharina
AU - Spinrath, Andreas
AU - Kostenis, Evi
AU - Zhao, Qiang
AU - Köse, Meryem
AU - Namasivayam, Vigneshwaran
AU - Müller, Christa E.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/9/27
Y1 - 2018/9/27
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.7b01768
DO - 10.1021/acs.jmedchem.7b01768
M3 - Article
C2 - 30048589
AN - SCOPUS:85050984274
SN - 0022-2623
VL - 61
SP - 8136
EP - 8154
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -
