Synthesis and pharmacological characterisation of a conformationally restrained series of indole-2-carboxylates as in vivo potent glycine antagonists.
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.
Fabio
R D
RD
GlaxoSmzithKline Group, GlaxoWellcome SpA, Medicines Research Centre, Verona, Italy. rdf26781@glaxowellcome.co.uk
Araldi
G
G
Baraldi
D
D
Cugola
A
A
Donati
D
D
Gastaldi
P
P
Giacobbe
S A
SA
Micheli
F
F
Pentassuglia
G
G
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D005998:Glycine / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000517:prevention & control; D020521:Stroke / Q000517:prevention & control; D013329:Structure-Activity Relationship
C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D007211:Indoles; D018696:Neuroprotective Agents; D005998:Glycine