GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo.
OBJECTIVE
Recently identified antagonists of the urotensin-II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.


METHODS
The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.


RESULTS
GSK1440115 (pK(i)= 7.34-8.64 across species) and GSK1562590 (pK(i)= 9.14-9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA(2)= 5.59-7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pK(b)= 8.93-10.12 across species), but a competitive antagonist in monkey arteries (pK(b)= 8.87-8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.


CONCLUSIONS
Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo.
Behm
D J
DJ
Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, PA, USA. david.j.behm@gsk.com
Aiyar
N V
NV
Olzinski
A R
AR
McAtee
J J
JJ
Hilfiker
M A
MA
Dodson
J W
JW
Dowdell
S E
SE
Wang
G Z
GZ
Goodman
K B
KB
Sehon
C A
CA
Harpel
M R
MR
Willette
R N
RN
Neeb
M J
MJ
Leach
C A
CA
Douglas
S A
SA
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology*; D002415:Cats; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000819:agonists; D015320:Tachykinins; D014579:Urotensins / Q000378:metabolism*; D014661:Vasoconstriction
C554432:4'-(1-(((6,7-dichloro-3- oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl)(methyl)amino)-2-(4-morpholinyl)ethyl)-4-biphenylcarboxylic acid; C554431:4'-(1-(((6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl)(methyl)amino)-2-(1-pyrrolidinyl)ethyl)-3-biphenylcarboxamide; D001549:Benzamides; D001565:Benzoates; D048588:Benzoxazines; D043562:Receptors, G-Protein-Coupled; D017473:Receptors, Opioid, kappa; D015320:Tachykinins; D014579:Urotensins; C029677:urotensin II