Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist

@article{Iglarz2008PharmacologyOM,
  title={Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist},
  author={Marc Iglarz and Christoph Binkert and Keith Morrison and Walter Fischli and John Gatfield and Alexander Treiber and Thomas J Weller and Martin H. Bolli and Christoph Boss and Stephan Buchmann and Bruno Capeleto and Patrick Hess and Changbin Qiu and Martine Clozel},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2008},
  volume={327},
  pages={736 - 745}
}
  • M. Iglarz, C. Binkert, +11 authors M. Clozel
  • Published 1 December 2008
  • Chemistry, Medicine
  • Journal of Pharmacology and Experimental Therapeutics
Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N′-propylaminosulfonamide], is a new dual ETA/ETB endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active… 
Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro.
TLDR
Although macitentan has a similar or higher potency for induction and inhibition of drug metabolising enzymes and transporters than bosentan, its low plasma concentrations and minimal accumulation in the liver suggest that it will be markedly less prone to drug-drug interactions.
Distinct ETA Receptor Binding Mode of Macitentan As Determined by Site Directed Mutagenesis
TLDR
Functional studies using ETA receptor variants harboring amino acid point mutations in the presumed ERA interaction site suggest that – in contrast to bosentan and ambrisentan - macitentan-ETA receptor binding is not dependent on strong charge-charge interactions, but depends predominantly on hydrophobic interactions.
Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension.
TLDR
The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.
Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension
TLDR
Results of pre-clinical data and studies in humans support the potential role of aprocitentan in patients with resistant hypertension and suggest the hypothesis that this new agent could expand the antihypertensive arsenal in resistant hypertension is an attractive candidate for further large-scale trials.
Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist
TLDR
Macitentan co-administered with Cs or rifampin was well tolerated and no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested were demonstrated.
Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects
TLDR
Macitentan metabolism is indeed affected by CYP3A4 inhibition, but the changes are not considered to be clinically significant and macitentan can be administered concomitantly with CYP2C19 isoenzyme without need for dose adjustment.
Macitentan: entry-into-humans study with a new endothelin receptor antagonist
TLDR
The pharmacokinetic and tolerability profile of macitentan is consistent with a once-a-day dosing regimen and warrants further investigation in clinical studies.
Does targeting the lipophilic milieu provide advantages for an endothelin antagonist?
TLDR
ET-1 acts mainly in a paracrine fashion and is an extremely potent and long-lasting vasoconstrictor and pressor effects that can induce hypertrophy and hyperplasia of cardiomyocytes, increase extracellular matrix production, and stimulate a pro-inflammatory phenotype.
Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries.
TLDR
The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries.
Endothelin-1, an Endogenous Irreversible Agonist in Search of an Allosteric Inhibitor
Endothelin-1 (ET-1), a 21 amino acid paracrine mediator and long-acting stimulus of G-protein coupled receptors (GPCRs), is implicated in cardiovascular diseases and cancers. We have recently
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