Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles.
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
McAtee
John J
JJ
Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com
Dodson
Jason W
JW
Dowdell
Sarah E
SE
Erhard
Karl
K
Girard
Gerald R
GR
Goodman
Krista B
KB
Hilfiker
Mark A
MA
Jin
Jian
J
Sehon
Clark A
CA
Sha
Deyou
D
Shi
Dongchuan
D
Wang
Feng
F
Wang
Gren Z
GZ
Wang
Ning
N
Wang
Yonghui
Y
Viet
Andrew Q
AQ
Yuan
Catherine C K
CC
Zhang
Daohua
D
Aiyar
Nambi V
NV
Behm
David J
DJ
Carballo
Luz H
LH
Evans
Christopher A
CA
Fries
Harvey E
HE
Nagilla
Rakesh
R
Roethke
Theresa J
TJ
Xu
Xiaoping
X
Douglas
Stephen A
SA
Neeb
Michael J
MJ
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D003959:Diamines / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D003959:Diamines; D017473:Receptors, Opioid, kappa; D014579:Urotensins; C029677:urotensin II