Improved synthesis of 4-/6-substituted 2-carboxy- 1H-indole-3-propionic acid derivatives and structure–activity relationships as GPR17 agonists† Younis Baqi, * a Samer Alshaibani, b Kirsten Ritter, b Aliaa Abdelrahman, b Andreas Spinrath, c Evi Kostenis c and Christa E. M ¨ uller * b The orphan G protein-coupled receptor GPR17 was shown to be involved in myelin repair and has been proposed as a novel drug target for the treatment of brain and spinal cord injury and for multiple sclerosis. Recently, 3-(2-carboxy-4,6-dichloro-indol-3-yl)propionic acid (MDL29,951, 1a) was discovered and characterized as a potent synthetic GPR17 agonist. In the present study we substantially optimized the preparation of 1a, which is carried out via Japp–Klingemann condensation of 3,5- dichlorophenyldiazonium chloride and deprotonated 2-(ethoxycarbonyl)cyclopentanone yielding phenylhydrazone derivative 5a followed by Fischer indole (diaza-Cope) rearrangement. A robust synthesis of 1a (75% yield) was developed to allow upscaling of the procedure. The developed method was applied to the synthesis of a series of 10 derivatives, eight of which represent new compounds. Biological evaluation in calcium mobilization assays using 1321N1-astrocytoma cells recombinantly expressing the human GPR17 provided first insights into their structure–activity relationships. 3-(2- Carboxy-4,6-dibromo-indol-3-yl)propionic acid (1b) showed similar potency to 1a and represents the most potent synthetic GPR17 agonist described to date with an EC 50 value of 202 nM. Introduction The orphan G protein-coupled receptor 17 (GPR17) belongs to the large family of rhodopsin-like class A G protein-coupled receptors (GPCRs). It is coupled to inhibition of adenylate cyclase via G i proteins resulting in decreased intracellular cAMP levels, and to G q proteins which activate phospholipase C leading to IP 3 -mediated intracellular calcium release. 1,2 GPR17 was recently shown to be involved in myelin repair and has therefore been proposed as a novel drug target for the treatment of multiple sclerosis, brain and spinal cord injury, and neuro- degenerative diseases. 2–6 Thus, the development of GPR17 modulators is of high pharmacological relevance. Several compounds have been postulated as physiological agonists of GPR17, including cysteinylleukotrienes (CysLTs) C4 and D4, UDPglucose, UDPgalactose, and UDP. 1 However, several groups, including ours, were unable to conrm the described effects. 2,4,7,8 Recently, Hennen et al. identied 3-(2-carboxy-4,6- dichloro-indol-3-yl)propionic acid (MDL29,951, 1a, Fig. 1) as a synthetic agonist for GPR17 and characterized it broadly in recombinant and native cells. 2 Compound 1a showed high potency at GPR17 in the nanomolar range; the determined EC 50 value was found to be dependent on the assay system and the receptor expression level. 2 The described synthesis of 1a provides only moderate overall yields. For extended studies of GPR17 using 1a as a tool compound, and for setting up a high-throughput (HTS) screening assay to identify GPR17 antagonists gram amounts of the agonist are required. Therefore the goal of the present study was to develop a signicantly improved synthetic procedure for 1a by carefully studying and optimizing the critical reaction steps. Furthermore, the new method was to be applied to the preparation of analogs to study their structure–activity rela- tionships (SARs). Fig. 1 The first reported synthetic GPR17 agonist. 2 a Department of Chemistry, Faculty of Science, Sultan Qaboos University, PO Box 36, Postal Code 123, Muscat, Oman. E-mail: baqi@squ.edu.om; Fax: +968 2414 1469; Tel: +968 2414 2347 b Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, Universit¨ at Bonn, Bonn, Germany. E-mail: christa.mueller@uni-bonn.de; Fax: +49 228 73 2567; Tel: +49 228 73 2301 c Institute of Pharmaceutical Biology, Section Molecular-, Cellular-, and Pharmacobiology, University of Bonn, Bonn, Germany † Electronic supplementary information (ESI) available: Analytical data of the di-ethyl ester indole derivatives (9a–j).See DOI: 10.1039/c3md00309d Cite this: Med. Chem. Commun. , 2014, 5, 86 Received 15th October 2013 Accepted 13th November 2013 DOI: 10.1039/c3md00309d www.rsc.org/medchemcomm 86 | Med. Chem. Commun. , 2014, 5, 86–92 This journal is © The Royal Society of Chemistry 2014 MedChemComm CONCISE ARTICLE Published on 22 November 2013. Downloaded on 30/01/2015 10:45:07. View Article Online View Journal | View Issue