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*

*المؤلف المقابل لهذا العمل

نتاج البحث: المساهمة في مجلةمقالمراجعة النظراء

18 اقتباسات (Scopus)

ملخص

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.

اللغة الأصليةEnglish
الصفحات (من إلى)8136-8154
عدد الصفحات19
دوريةJournal of Medicinal Chemistry
مستوى الصوت61
رقم الإصدار18
المعرِّفات الرقمية للأشياء
حالة النشرPublished - سبتمبر 27 2018

ASJC Scopus subject areas

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بصمة

أدرس بدقة موضوعات البحث “3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17'. فهما يشكلان معًا بصمة فريدة.

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