Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists.
The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha, gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi=7.2) as well as very potent antagonistic activity (pA2=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.
Solvay Pharmaceuticals, Research Laboratories, Weesp, The Netherlands.
Axel Reinhard
AR
Stoit
Jos Hubertus Maria
JH
Lange
Arnold Peter den
AP
Hartog
Eric
E
Ronken
Koos
K
Tipker
Herman Heinrich van
HH
Stuivenberg
Jessica Adriana Rigtje
JA
Dijksman
Henri Cornelis
HC
Wals
Chris Gerrit
CG
Kruse
D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*
D002186:Cannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug