CoMFA, synthesis, and pharmacological evaluation of (E)-3-(2-carboxy-2-arylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acids: 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, a potent selective glycine-site NMDA receptor antagonist.
(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.
Baron
Bruce M
BM
Department of Medicinal Chemistry, Aventis Pharmaceuticals, Route 202-206, Bridgewater, New Jersey 08807-0800, USA.
Cregge
Robert J
RJ
Farr
Robert A
RA
Friedrich
Dirk
D
Gross
Raymond S
RS
Harrison
Boyd L
BL
Janowick
David A
DA
Matthews
Donald
D
McCloskey
Timothy C
TC
Meikrantz
Scott
S
Nyce
Philip L
PL
Vaz
Roy
R
Metz
William A
WA
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D005998:Glycine / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013237:Stereoisomerism; D020521:Stroke / Q000188:drug therapy / Q000473:pathology
C498565:3-(2-(3-aminophenyl)-2-carboxyvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid; D000927:Anticonvulsants; D002264:Carboxylic Acids; D007211:Indoles; D018696:Neuroprotective Agents; D010648:Phenylacetates; D016194:Receptors, N-Methyl-D-Aspartate; D006152:Cyclic GMP; D005998:Glycine