The Discovery of <i>N</i>-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-<i>N</i>′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist

Bolli, Martin H.; Boss, Christoph; Binkert, Christoph A.; Blüml, Stephan; Bur, Daniel; Hess, Patrick; Iglarz, Marc; Meyer, Solange; Rein, Josiane; Rey, Markus; Treiber, Alexander; Clozel, Martine; Fischli, Walter; Weller, Thomas

doi:10.1021/jm3009103

Cited by 125 publications

(86 citation statements)

References 52 publications

(98 reference statements)

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“…In 2013, the novel dual ERA macitentan (Opsumit) [15] demonstrated efficacy in a long-term event-driven phase 3 clinical trial [16] and has recently received marketing authorisation in many countries. Macitentan is significantly less acidic (pKa = 6.2) than bosentan (pKa = 5.1) and ambrisentan (pKa = 3.5) and more lipophilic (logD = 2.9 compared to logD = −0.4 for ambrisentan and logD = 1.3 for bosentan) [17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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The competitive endothelin receptor antagonists (ERA) bosentan and ambrisentan, which have long been approved for the treatment of pulmonary arterial hypertension, are characterized by very short (1 min) occupancy half-lives at the ETA receptor. The novel ERA macitentan, displays a 20-fold increased receptor occupancy half-life, causing insurmountable antagonism of ET-1-induced signaling in pulmonary arterial smooth muscle cells. We show here that the slow ETA receptor dissociation rate of macitentan was shared with a set of structural analogs, whereas compounds structurally related to bosentan displayed fast dissociation kinetics. NMR analysis showed that macitentan adopts a compact structure in aqueous solution and molecular modeling suggests that this conformation tightly fits into a well-defined ETA receptor binding pocket. In contrast the structurally different and negatively charged bosentan-type molecules only partially filled this pocket and expanded into an extended endothelin binding site. To further investigate these different ETA receptor-antagonist interaction modes, we performed functional studies using ETA receptor variants harboring amino acid point mutations in the presumed ERA interaction site. Three ETA receptor residues significantly and differentially affected ERA activity: Mutation R326Q did not affect the antagonist activity of macitentan, however the potencies of bosentan and ambrisentan were significantly reduced; mutation L322A rendered macitentan less potent, whereas bosentan and ambrisentan were unaffected; mutation I355A significantly reduced bosentan potency, but not ambrisentan and macitentan potencies. This suggests 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. This different binding mode could be the reason for macitentan's sustained target occupancy and insurmountable antagonism.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…In preclinical and clinical studies macitentan showed (1) sustained receptor binding [1], high potency, and tissue penetration properties [2], (2) excellent pharmacokinetic (PK) properties [3,4,5], (3) low potential for interaction with other drugs at the level of cytochrome P450 enzymes and organic anion-transporting polypeptide transporters [6,7], and (4) no need for dose adjustment in patients with hepatic or renal impairment [8,9]. …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Macitentan in Caucasian and Japanese Subjects: The Influence of Ethnicity and Sex

et al. 2013

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Background/Aims: Macitentan is a novel dual endothelin receptor antagonist with sustained receptor binding in clinical development for pulmonary arterial hypertension. The present study compared the pharmacokinetics and safety of macitentan in healthy Caucasian and Japanese subjects and explored the potential sex differences. Methods: In this single-center, open-label, phase I study 10 healthy subjects of each ethnic origin with a male/female ratio of 1:1 in each group were administered a single oral 10-mg dose of macitentan. Blood samples were taken to determine plasma levels of macitentan and its pharmacologically active metabolite, ACT-132577, and safety and tolerability were monitored using standard assessments. Results: For both macitentan and its metabolite, values for C_max were similar but a shorter half-life was determined in Japanese subjects resulting in an exposure to both compounds being approximately 15% lower in Japanese when compared to Caucasian subjects. The exposure to macitentan was similar in Japanese males and females whereas Caucasian females had an approximately 25% higher exposure than Caucasian males. In both ethnic groups, females had an approximately 15% higher exposure to ACT-132577 than male subjects. Macitentan was well tolerated in both ethnic groups. There were no clinically significant differences in adverse event profile, clinical laboratory, electrocardiographic parameters, and vital signs between both groups. Conclusion: The data suggest that the minor differences in pharmacokinetics between the two groups are not clinically relevant and no dose adjustment of macitentan based on Japanese ethnic origin or sex is necessary.

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“…Macitentan does not inhibit canalicular bile acid transport in rats, which could lead to a better liver safety profile than bosentan [96]. In the SERAPHIN study, the incidence of aminotransferase levels more than three times the upper limit of normal were similar to that of the placebo group [87].…”

Section: Elevation In Hepatic Aminotransferasesmentioning

confidence: 94%

Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

Chaumais

Guignabert

Savale

et al. 2014

Am J Cardiovasc Drugs

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Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH.

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The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist

Cited by 125 publications

References 52 publications

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

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

Pharmacokinetics of Macitentan in Caucasian and Japanese Subjects: The Influence of Ethnicity and Sex

Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

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