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.
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
John J
JJ
McAtee
Jason W
JW
Dodson
Sarah E
SE
Dowdell
Karl
K
Erhard
Gerald R
GR
Girard
Krista B
KB
Goodman
Mark A
MA
Hilfiker
Jian
J
Jin
Clark A
CA
Sehon
Deyou
D
Sha
Dongchuan
D
Shi
Feng
F
Wang
Gren Z
GZ
Wang
Ning
N
Wang
Yonghui
Y
Wang
Andrew Q
AQ
Viet
Catherine C K
CC
Yuan
Daohua
D
Zhang
Nambi V
NV
Aiyar
David J
DJ
Behm
Luz H
LH
Carballo
Christopher A
CA
Evans
Harvey E
HE
Fries
Rakesh
R
Nagilla
Theresa J
TJ
Roethke
Xiaoping
X
Xu
Stephen A
SA
Douglas
Michael J
MJ
Neeb
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