Thiazole as a Carbonyl Bioisostere. A Novel Class of Highly Potent and Selective 5-HT3 Receptor Antagonists

Article abstract of DOI:10.1021/jm00172a006

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.