Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).
Yang
Zhicai
Z
Discovery R&D AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Fairfax
David J
DJ
Maeng
Jun-Ho
JH
Masih
Liaqat
L
Usyatinsky
Alexander
A
Hassler
Carla
C
Isaacson
Soshanna
S
Fitzpatrick
Kevin
K
DeOrazio
Russell J
RJ
Chen
Jianqing
J
Harding
James P
JP
Isherwood
Matthew
M
Dobritsa
Svetlana
S
Christensen
Kevin L
KL
Wierschke
Jonathan D
JD
Bliss
Brian I
BI
Peterson
Lisa H
LH
Beer
Cathy M
CM
Cioffi
Christopher
C
Lynch
Michael
M
Rennells
W Martin
WM
Richards
Justin J
JJ
Rust
Timothy
T
Khmelnitsky
Yuri L
YL
Cohen
Marlene L
ML
Manning
David D
DD
D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology*
D001583:Benzoxazoles; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists