Journal of Medicinal Chemistry · 2012 · 148 citations · 34 references
PharmacyMedicinal ChemistryPharmacologyClinical PharmacologyDrug DesignDrug DiscoveryCardiovascular PharmacologyHypertension PharmacotherapyLead Compound DesignPulmonary HypertensionReceptor PharmacologyStructure-activity Relationship AnalysisAntihypertensive PharmacologyEndothelin Receptor AntagonistsIn Vivo Efficacy TestingMedicinal Chemistry ApplicationsPhase Iii Clinical TrialsPulmonary Hypertension PharmacologyPyrimidine AnaloguesSalt-sensitive Hypertension
Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.
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A novel potent vasoconstrictor peptide produced by vascular endothelial cells
Masashi Yanagisawa, Hiroki Kurihara, Sadao Kimura et al. · Nature · 1988 · 10.8K citations · Full text
Akiko Inoue, Masashi Yanagisawa, Sadao Kimura et al. · Proceedings of the National Academy of Sciences · 1989 · 2.5K citations · Full text