1.
J Med Chem
; 33(10): 2715-20, 1990 Oct.
Article
in English
| MEDLINE
| ID: mdl-2213824
ABSTRACT
A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Thiazoles/pharmacology , Administration, Oral , Animals , Computer Graphics , In Vitro Techniques , Mice , Models, Molecular , Neurons/metabolism , Radioligand Assay , Rats , Receptors, Serotonin/classification , Serotonin Antagonists/metabolism , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Thiazoles/administration & dosage , Thiazoles/chemistry , Tumor Cells, Cultured
2.
J Med Chem
; 33(1): 13-6, 1990 Jan.
Article
in English
| MEDLINE
| ID: mdl-2296012