GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo

作者：Behm D J^*; Aiyar N V; Olzinski A R; McAtee J J; Hilfiker M A; Dodson J W; Dowdell S E; Wang G Z; Goodman K B; Sehon C A; Harpel M R; Willette R N; Neeb M J; Leach C A; Douglas S A

来源：British Journal of Pharmacology, 2010, 161(1): 207-228.

DOI：10.1111/j.1476-5381.2010.00889.x

• urotensin-II
• UT
• GSK1562590
• GSK1440115
• antagonist
• blood pressure
• G-protein-coupled receptor
• residence time
• dissociation rate
• biochemical efficiency

BACKGROUND AND PURPOSE
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.
EXPERIMENTAL APPROACH
The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.
KEY 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 AND IMPLICATIONS
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.

• 出版日期2010-9