Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists.
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.
Rosen
T
T
Pfizer central Research, Department of Medicinal Chemistry, Groton, Connecticut 06340.
Nagel
A A
AA
Rizzi
J P
JP
Ives
J L
JL
Daffeh
J B
JB
Ganong
A H
AH
Guarino
K
K
Heym
J
J
McLean
S
S
Nowakowski
J T
JT
D000284:Administration, Oral; D000818:Animals; D003196:Computer Graphics; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles