3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17

被引：20

作者：

Baqi, Younis ^{[1
]}

Pillaiyar, Thanigaimalai ^{[2
]}

Abdelrahman, Aliaa ^{[2
]}

Kaufmann, Olesja ^{[2
]}

Aishaibani, Samer ^{[2
]}

Rafehi, Muhammad ^{[2
]}

Ghasimi, Saman ^{[2
]}

Akkari, Rhalid ^{[2
]}

Ritter, Kirsten ^{[2
]}

Simon, Katharina ^{[3
]}

Spinrath, Andreas ^{[3
]}

Kostenis, Evi ^{[3
]}

Zhao, Qiang ^{[4
]}

Koese, Meryem ^{[2
]}

Namasivayam, Vigneshwaran ^{[2
]}

Mueller, Christa E. ^{[2
]}

机构：

[1] Sultan Qaboos Univ, Fac Sci, Dept Chem, POB 36, Muscat 123, Oman

[2] Univ Bonn, Pharmaceut Chem 1, PSB, Pharmaceut Inst,Pharmactr Bonn, Immenburg 4, D-53121 Bonn, Germany

[3] Univ Bonn, Inst Pharmaceut Biol Sect Mol Cellular & Pharmaco, Nussallee 6, D-53115 Bonn, Germany

[4] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 18期

关键词：

HUMAN P2Y(12) RECEPTOR; GPCR DRUG DISCOVERY; NEURODEGENERATIVE DISEASES; CYSTEINYL LEUKOTRIENES; URACIL NUCLEOTIDES; ACCURATE DOCKING; ANTAGONISTS; INHIBITORS; MEMBRANES; DATABASE;

D O I：

10.1021/acs.jmedchem.7b01768

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：8136 / 8154

页数：19

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