Design, syntheses, and structure-activity relationships of indan derivatives as endothelin antagonists; new lead generation of non-peptidic antagonist from peptidic leads.
A new lead generation of non-peptidic ET(A) antagonists from two peptidic ET(A)-selective ones, BQ-123 and FR139317, was performed. Using computer assisted molecular modeling, a putative pharmacophore was constructed from the superposition of the reported three-dimensional structure of the cyclic peptide BQ-123 and a presumable beta-turn active conformation of the linear peptide FR139317 formed by an intramolecular hydrogen bond. According to this model, a new series of indan derivatives were designed and synthesized. Among these, 5-isobutyrylamino-6-(1-naphthylmethyloxy)-3-(2-thienyl)-1-indancarboxylic acid (1b) showed a moderate ET(A) antagonistic activity (IC50 = 28 microM).
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd, Saitama, Japan.
H
H
Morimoto
C
C
Fukushima
R
R
Yamauchi
T
T
Hosino
K
K
Kikkawa
K
K
Yasuda
K
K
Yamada
D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001381:Azepines; D015195:Drug Design; D016232:Endothelins / Q000037:antagonists & inhibitors*; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic; D011485:Protein Binding; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D001381:Azepines; D016232:Endothelins; D007189:Indans; D007211:Indoles; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C079574:FR 139317; C072247:cyclo(Trp-Asp-Pro-Val-Leu)