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Design, synthesis, and structure–activity relationships of indole-3-heterocycles as agonists of the CB1 receptor

2010; Elsevier BV; Volume: 21; Issue: 1 Linguagem: Inglês

10.1016/j.bmcl.2010.10.093

1464-3405

Angus J. Morrison, Julia M. Adam, James Α. Baker, Robert A. Campbell, John K. Clark, Jean E. Cottney, Maureen R. Deehan, Anna-Marie Easson, Ruth Fields, Stuart Francis, Fiona Jeremiah, Neil S. Keddie, Takao Kiyoi, Duncan McArthur, Karsten Meyer, Paul Ratcliffe, Jürgen Schulz, Grant Wishart, Kazuya Yoshiizumi,

Adenosine and Purinergic Signaling

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.