Improved synthesis of 4-/6-substituted 2-carboxy-1H-indole-3-propionic acid derivatives and structure–activity relationships as GPR17 agonists?

MedChemComm Pub Date: 2013-11-22 DOI: 10.1039/C3MD00309D

Abstract

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 EC50 value of 202 nM.

Graphical abstract: Improved synthesis of 4-/6-substituted 2-carboxy-1H-indole-3-propionic acid derivatives and structure–activity relationships as GPR17 agonists
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