Development of potent and selective small-molecule human Urotensin-II antagonists.
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
McAtee
John J
JJ
Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com
Dodson
Jason W
JW
Dowdell
Sarah E
SE
Girard
Gerald R
GR
Goodman
Krista B
KB
Hilfiker
Mark A
MA
Sehon
Clark A
CA
Sha
Deyou
D
Wang
Gren Z
GZ
Wang
Ning
N
Viet
Andrew Q
AQ
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
Yuan
Catherine C K
CC
Douglas
Stephen A
SA
Neeb
Michael J
MJ
D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D008970:Molecular Weight; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C530869:(3,4-dichlorophenyl)methyl(2-oxo-2-(3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl)ethyl)amine; D000814:Aniline Compounds; D010881:Piperidones; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; C121697:UTS2R protein, human