218601-34-4

Upstream product

• 90220-25-0 3-phenyl-1-propane-sulfonamide 
• 150728-13-5 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine 
• 329923-15-1 4,6-dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine 
• 20730-58-9 2-(2-Methoxyphenoxy)propanedioic acid diethyl ester 

Downstream Products

• 405307-83-7 C₂₆H₂₇N₅O₆S 

Relevant academic research and scientific papers

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

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 ETA 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.

Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ETA -selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ETA binding affinity and ETA selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3 mg /kg with a duration of > 6.5 h. Compound 6e also exhibited a potent antagonisti activity in the pithed rats. Copyright