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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-01, Vol.21 (1), p.506-509
Hauptverfasser:	Morrison, Angus J., Adam, Julia M., Baker, James A., Campbell, Robert A., Clark, John K., Cottney, Jean E., Deehan, Maureen, Easson, Anna-Marie, Fields, Ruth, Francis, Stuart, Jeremiah, Fiona, Keddie, Neil, Kiyoi, Takao, McArthur, Duncan R., Meyer, Karsten, Ratcliffe, Paul D., Schulz, Jurgen, Wishart, Grant, Yoshiizumi, Kazuya
Format:	Artikel
Sprache:	eng
Schlagworte:	agonists Animals Biological and medical sciences Cannabinoid CB1 receptor Drug Design GPCR agonist Heterocyclic Compounds - chemical synthesis Heterocyclic Compounds - chemistry Heterocyclic Compounds - pharmacokinetics Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacokinetics Medical sciences Mice Microsomes - metabolism Miscellaneous Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments piperazine Receptor, Cannabinoid, CB1 - agonists Receptor, Cannabinoid, CB1 - metabolism Structure-Activity Relationship structure-activity relationships tail Thiadiazoles - chemical synthesis Thiadiazoles - chemistry Thiadiazoles - pharmacokinetics
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.10.093