Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides.
This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.
Youssefyeh
R D
RD
Rhône-Poulenc Rorer Central Research, King of Prussia, Pennsylvania 19406.
Campbell
H F
HF
Klein
S
S
Airey
J E
JE
Darkes
P
P
Powers
M
M
Schnapper
M
M
Neuenschwander
K
K
Fitzpatrick
L R
LR
Pendley
C E
CE
D000818:Animals; D000932:Antiemetics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D005289:Ferrets; D017829:Granisetron; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000378:metabolism; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology / Q000627:therapeutic use; D015394:Molecular Structure; D017294:Ondansetron; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D000932:Antiemetics; D001549:Benzamides; D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002945:Cisplatin; D017829:Granisetron; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D008787:Metoclopramide; D017294:Ondansetron; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C059068:GR 65630; C073522:N-(1-azabicyclo(2.2.2)-oct-3-yl)-5-chlorospiro(benzofuran-2(3H),1'-cyclohexane)-7-carboxamide