ABSTRACT
After the identification of GV150526, the indole-2-carboxylate template was further explored in order to identify novel potential anti-stroke agents. In particular, the SAR of the side chain present at the C-3 position of the indole nucleus was widely studied. In this paper, the synthesis and the pharmacological profile of a further class of conformationally restricted analogues of GV150526 as in vitro and in vivo potent glycine antagonists is reported. In particular, a pyrazolidinone derivative was identified as a potent neuroprotective agent in animal models of cerebral ischaemia.
Subject(s)
Glycine/antagonists & inhibitors , Indoles/chemical synthesis , Animals , Binding Sites/drug effects , Indoles/pharmacology , Male , Mice , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/therapeutic use , Rats , Rats, Sprague-Dawley , Seizures/prevention & control , Stroke/prevention & control , Structure-Activity RelationshipABSTRACT
Compounds 2 and 3 were designed in order to probe the North-East region of the strichnine-insensitive glycine binding site of the NMDA receptor. The two products were obtained readily by a tandem aldol condensation-lactonization-elimination step which affords the desired E isomer with complete regioselection.