Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles

McAtee, John J.; Dodson, Jason W.; Dowdell, Sarah E.; Erhard, Karl F.; Girard, G. R.; Goodman, Krista B.; Hilfiker, Mark A.; Jin, Jian; Sehon, Clark A.; Sha, Deyou; Shi, Dongchuan; Wang, Feng; Wang, Gren Z.; Wang, Ning; Wang, Yonghui; Viet, Andrew Q.; Yuan, Catherine C.K.; Zhang, Dao Hua; Aiyar, Nambi; Behm, David J.; Carballo, Luz H.; Evans, Christopher A.; Fries, Harvey E.; Nagilla, Rakesh; Roethke, Theresa J.; Xu, Xiaoping; Douglas, Stephen A.; Neeb, Michael J.

doi:10.1016/j.bmcl.2008.05.058

Cited by 8 publications

(1 citation statement)

References 37 publications

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“…It is therefore reasonable to hypothesize that this interaction may be accentuated with GSK1562590 due to the presence of the more basic pyrrolidine residue compared with the less basic morpholine in GSK1440115. Indeed, comparison of numerous pairs of pyrrolidine/morpholine analogs having otherwise identical chemical structures has demonstrated that without exception, the pyrrolidine analogues are 10–1000‐fold more potent than their morpholine counterparts (McAtee et al ., 2008). In addition, a set of analogues in this chemical series with basic moieties other than pyrrolidine and morpholine exhibited a strong correlation between the basicity of the nitrogen functionality and UT binding affinity (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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

Behm

Aiyar

Olzinski

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSERecently 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 APPROACHThe pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays. KEY RESULTSGSK1440115 (pKi = 7.34-8.64 across species) and GSK1562590 (pKi = 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 (pA2 = 5.59-7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pKb = 8.93-10.12 across species), but a competitive antagonist in monkey arteries ). 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 IMPLICATIONSWhereas 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.

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Section: Discussionmentioning

confidence: 99%

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

Behm

Aiyar

Olzinski

et al. 2010

British J Pharmacology

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Tandem Ugi MCR/Mitsunobu Cyclization as a Short, Protecting‐Group‐Free Route to Benzoxazinones with Four Diversity Points

et al. 2010

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A tandem Ugi/Mitsunobu protocol, starting from o‐aminophenols, α‐hydroxy acids, amines and aldehydes gives benzo[b][1,4]oxazin‐3‐ones of general formula 1 in two high‐yielding steps, with the introduction of up to four diversity inputs. The mildness of the methodology allows the stereospecific synthesis of enantiomerically pure products as well as the introduction of additional functional groups. The overall procedure can also be carried out in a one‐pot manner.

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Optimization of isochromanone based urotensin II receptor agonists

Lehmann

Currier

Olsson

et al. 2010

Bioorganic & Medicinal Chemistry

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Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles

Cited by 8 publications

References 37 publications

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

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

Tandem Ugi MCR/Mitsunobu Cyclization as a Short, Protecting‐Group‐Free Route to Benzoxazinones with Four Diversity Points

Optimization of isochromanone based urotensin II receptor agonists

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