3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives

Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17

Younis Baqi, Thanigaimalai Pillaiyar, Aliaa Abdelrahman, Olesja Kaufmann, Samer Alshaibani, Muhammad Rafehi, Saman Ghasimi, Rhalid Akkari, Kirsten Ritter, Katharina Simon, Andreas Spinrath, Evi Kostenis, Qiang Zhao, Meryem Köse, Vigneshwaran Namasivayam, Christa E. Müller

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8136-8154
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Issue number18
DOIs
Publication statusPublished - Sep 27 2018

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G-Protein-Coupled Receptors
Structure-Activity Relationship
Molecular Dynamics Simulation
Pharmaceutical Preparations
indole-2-carboxylic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives : Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17. / 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; Köse, Meryem; Namasivayam, Vigneshwaran; Müller, Christa E.

In: Journal of Medicinal Chemistry, Vol. 61, No. 18, 27.09.2018, p. 8136-8154.

Research output: Contribution to journalArticle

Baqi, Y, Pillaiyar, T, Abdelrahman, A, Kaufmann, O, Alshaibani, S, Rafehi, M, Ghasimi, S, Akkari, R, Ritter, K, Simon, K, Spinrath, A, Kostenis, E, Zhao, Q, Köse, M, Namasivayam, V & Müller, CE 2018, '3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17', Journal of Medicinal Chemistry, vol. 61, no. 18, pp. 8136-8154. https://doi.org/10.1021/acs.jmedchem.7b01768
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 ; Köse, Meryem ; Namasivayam, Vigneshwaran ; Müller, Christa E. / 3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives : Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 18. pp. 8136-8154.
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abstract = "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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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.

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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DO - 10.1021/acs.jmedchem.7b01768

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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