A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties.
We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
Moss
Neil
N
Department of Medicinal Chemistry, Cardiovascular Disease, or Drug Discovery Support, Boehringer Ingelheim Pharmaceutical, Inc, Ridgefield, CT 06877, United States. nmoss@rdg.boehringer-ingelheim.com
Choi
Younggi
Y
Cogan
Derek
D
Flegg
Adam
A
Kahrs
Andreas
A
Loke
Pui
P
Meyn
Orietta
O
Nagaraja
Raj
R
Napier
Spencer
S
Parker
Ashley
A
Thomas Peterson
J
J
Ramsden
Philip
P
Sarko
Christopher
C
Skow
Donna
D
Tomlinson
Josh
J
Tye
Heather
H
Whitaker
Mark
M
D000818:Animals; D001665:Binding Sites; D008297:Male; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000145:classification / Q000493:pharmacokinetics*
D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists