3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17
文献类型：期刊论文
| 作者 | Baqi, Younis2; Pillaiyar, Thanigaimalai1; Abdelrahman, Aliaa1; Kaufmann, Olesja1; Aishaibani, Samer1; Rafehi, Muhammad1; Ghasimi, Saman1; Akkari, Rhalid1; Ritter, Kirsten1; Simon, Katharina4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2018-09-27 |
| 卷号 | 61期号:18页码:8136-8154 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.7b01768 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | HUMAN P2Y(12) RECEPTOR ; GPCR DRUG DISCOVERY ; NEURODEGENERATIVE DISEASES ; CYSTEINYL LEUKOTRIENES ; URACIL NUCLEOTIDES ; ACCURATE DOCKING ; ANTAGONISTS ; INHIBITORS ; MEMBRANES ; DATABASE |
| 资助项目 | Sultan Qaboos University (SQU)[SR/SCI/CHEM/15/01] ; Arab-German Young Academy (AGYA)[AGYA_2017_TP_02] ; Arab-German Young Academy (AGYA)[AGYA_2017_TP_07] ; Arab-German Young Academy (AGYA)[AGYA_2017_TP_13] ; Alexander von Humboldt Foundation[00000000] ; Bayer Pharma[00000000] ; BMBF (German Federal Ministry for Education and Research) within the BioPharma initiative "Neuroallianz"[00000000] ; UCB (Union Chimique Belge)[00000000] ; Evangelisches Studienwerk eV[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000446142000006 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279569]  |
| 专题 | 药物靶标结构与功能中心 |
| 作者单位 | 1.Univ Bonn, Pharmaceut Chem 1, PSB, Pharmaceut Inst,Pharmactr Bonn, Immenburg 4, D-53121 Bonn, Germany; 2.Sultan Qaboos Univ, Fac Sci, Dept Chem, POB 36, Muscat 123, Oman; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Univ Bonn, Inst Pharmaceut Biol Sect Mol Cellular & Pharmaco, Nussallee 6, D-53115 Bonn, Germany; |
| 推荐引用方式 GB/T 7714 | Baqi, Younis,Pillaiyar, Thanigaimalai,Abdelrahman, Aliaa,et al. 3-(2-Carboxyethyl)indole-2-carboxylic Acid Derivatives: Structural Requirements and Properties of Potent Agonists of the Orphan G Protein-Coupled Receptor GPR17[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(18):8136-8154. |
| APA | Baqi, Younis.,Pillaiyar, Thanigaimalai.,Abdelrahman, Aliaa.,Kaufmann, Olesja.,Aishaibani, Samer.,...&Mueller, Christa E..(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,61(18),8136-8154. |
| MLA | Baqi, Younis,et al."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 61.18(2018):8136-8154. |
入库方式： OAI收割
来源：上海药物研究所
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