Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists

Axel Reinhard Stoit, Jos Hubertus Maria Lange, Arnold Peter den Hartog, Eric Ronken, Koos Tipker, Herman Heinrich van Stuivenberg, Jessica Adriana Rigtje Dijksman, Henri Cornelis Wals, Chris Gerrit Kruse
2002 Chemical and pharmaceutical bulletin  
The design, synthesis and biological activities of potent pyrazole-based tricyclic CB 1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated a a,g g-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB 1 receptor affinity (pK i ‫)2.7؍‬ as well as very potent antagonistic activity (pA 2 ‫)8.8؍‬ in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic
more » ... aromatic substitution pattern of the applied arylhydrazine.
doi:10.1248/cpb.50.1109 pmid:12192147 fatcat:ueoil45m6zfjjp33lshaom5yki