Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists

Julia M. Adam; Jim Cairns; Wilson Caulfield; Phillip Cowley; Iain Cumming; Morag Easson; Darren Edwards; Morag Ferguson; Richard Goodwin; Fiona Jeremiah; Takao Kiyoi; Ashvin Mistry; Elizabeth Moir; Richard Morphy; Jason Tierney; Mark York; James Baker; Jean E. Cottney; Andrea K. Houghton; Paul J. Westwood; Glenn Walker

doi:10.1039/C0MD00022A

Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptoragonists†

Julia M. Adam,*^a Jim Cairns,^a Wilson Caulfield,^a Phillip Cowley,^a Iain Cumming,^a Morag Easson,^a Darren Edwards,^a Morag Ferguson,^a Richard Goodwin,^a Fiona Jeremiah,^a Takao Kiyoi,^a Ashvin Mistry,^a Elizabeth Moir,^a Richard Morphy,^a Jason Tierney,^a Mark York,^a James Baker,^b Jean E. Cottney,^b Andrea K. Houghton,^b Paul J. Westwood^b and Glenn Walker^b

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* Corresponding authors

^a Department of Chemistry, Schering-Plough Research Institute, Newhouse, Lanarkshire, UK
E-mail: julia.adam@spcorp.com
Fax: +44 1698 736187
Tel: +44 1698 736000

^b Department of Pharmacology, Schering-Plough Research Institute, Newhouse, Lanarkshire, UK

Abstract

A novel CB1 receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water solubility. Structural variations were explored with the aim of introducing water solubility and improving potency. This led to the discovery of Org 28611, a potent, water soluble CB1 receptor agonist, which was selected for clinical evaluation as a potential intravenous analgesic agent.

MedChemComm

Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptoragonists†

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Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists

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