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 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. IglarzC. Binkert M. Clozel
  • Published 1 December 2008
  • Biology, Medicine, Chemistry
  • 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… 

Figures and Tables from this paper

Pipersentan: A De Novo Synthetic Endothelin Receptor Antagonist that Inhibits Monocrotaline- and Hypoxia-Induced Pulmonary Hypertension

Pipersentan efficaciously antagonized the effects of ET-1 on pulmonary artery smooth muscle cell proliferation, migration and calcium mobilization and effectively improved right ventricular hypertrophy and pulmonary arterial pressure in both monocrotaline- and hypoxia-induced pulmonary hypertension (PH) rat models.

Distinct ETA Receptor Binding Mode of Macitentan As Determined by Site Directed Mutagenesis

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.

Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension

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

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

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.

Does targeting the lipophilic milieu provide advantages for an endothelin antagonist?

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.

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

It is suggested that allosteric inhibitors of the agonist-binding or of the activation of the secondary quasi-irreversible site might be better suited for the treatment of ET-1-related diseases than inhibitors of endothelin-converting enzyme and competitive ET-receptor antagonists.
...

References

SHOWING 1-10 OF 51 REFERENCES

Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use.

Tezosentan, a potent mixed ET receptor antagonist with a short half-life, may offer a novel medical approach for the i.v. treatment of acute pathological conditions.

Are There Different ETB Receptors Mediating Constriction and Relaxation?

It is suggested that the endothelial ETB receptor mediating dilatation and the smooth muscle cell ETBceptor mediating constriction may not represent two different subtypes of ETB receptors.

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers*

The data suggest that ETA and ETB receptors form constitutive heterodimers, which show a slower sequestration of the ETBflag·YFP receptors upon stimulation with ET-1 than with BQ3020.

Gene expression, localization, and characterization of endothelin A and B receptors in the human adrenal cortex.

The genes of ET-1 and both its receptor sub types ETA and ETB are actively transcribed in the human adrenal cortex and both receptor subtypes are translated into proteins in ZG and APA cells.

The pharmacology of bosentan.

Bosentan is a combined and competitive antagonist of both ETA and ETB receptors that is selective for the endothelin system that potently antagonises the vascular response elicited by the endothelins in vitro and in vivo.

Effectiveness of a Nonselective ETA/B and a Selective ETA Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension

Both the nonselective ETA/B antagonist BSF420627 and the selective ETA antagonist LU135252 are effective in this model of PH.

Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade.

In human SMCs,ET-1 markedly potentiates proliferation to PDGF, mainly via ETA receptors, which may represent an important function of ET-1 for vascular structural changes in patients and provide new therapeutic opportunities for ET- 1 receptor antagonists.

Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade.

Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo, which appears to result in major part from an increase in nitric oxide generation.

Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis

Observations suggest an enhanced ET-1–mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ETB-mediated vasoconstriction.
...