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 - Funding Information:
Y.B. is grateful for Sultan Qaboos University (SQU) grant (SR/ SCI/CHEM/15/01) and Arab?German Young Academy (AGYA) grants (AGYA-2017-TP-02, AGYA-2017-TP-07, and AGYA-2017-TP-13). T.P. thanks the Alexander von Humboldt foundation and Bayer Pharma for a postdoctoral fellowship. A.A., E.K., and C.E.M. were supported by the BMBF (German Federal Ministry for Education and Research) within the BioPharma initiative "Neuroallianz" and by UCB (Union Chimique Belge). K.R. was supported by Evangelisches Studienwerk eV (Ph.D. scholarship). We thank Stefanie Weyer and Katharina Sylvester for expert technical assistance and Schro?dinger Inc. for providing the evaluation license.
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 -