Endothelin (ET), isolated from the conditioned medium of cultured porcine vascular endothelial cells in 1988, is a highly potent vasoconstrictive 21-amino acid peptide.3) There are three isoforms (ET-1, ET-2, ET-3). ET-1 is the predominant component of the three ET-isopeptides and is derived from precursor big ET-1.4) ET-1 has been believed to be implicated in the pathogenesis of various diseases, largely because of its ability to constrict vascular and nonvascular smooth muscle. 5)Two subtypes of receptors for ETs , termed the ET A receptor and ET B receptor, have been cloned and stably expressed in mammals. ET A receptor appears to exhibit affinity for ET-1 and ET-2 over ET-3, whereas the ET B receptor has nearly equipotent affinity for these three ETs. 6)A number of ET A -selective and ET A /ET B mixed antagonists have been reported for a decade, 7) and some of these ET antagonists are currently in clinical trials.In the previous paper, 8) we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ET A -selective ET receptor antagonists, including the compounds (1a, b) (Fig. 1). Among these, the potassium salt of 1a (YM598 monopotassium) is in clinical trials. Compound 1a showed an IC 50 value of 3.1 nM for the ET A receptor and 1200 nM for the ET B receptor (ET B /ET A ratioϭ390). In the in vivo study, it showed a potent oral inhibitory activity of pressor response to big ET-1-treated rats and excellent pharmacokinetic profiles in rats and dogs. In this paper, we wish to report the investigation of the further details of the structureactivity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a.In the previous study, 8b) replacement of the phenyl group of the 2-phenylethenesulfonmamide moiety in compound 1a with another aryl or heteroaryl groups was explored. This exercise revealed that these modifications were well tolerated in the ET A binding affinity and remarkably led to various ET B /ET A ratios in the 50-820 range. Intrigued by these observations, we became interested in the effect of the further modification of the phenyl group in the phenylethenesulfonamide moiety of 1a on both ET A and ET B binding affinities and the ET A /ET B ratio. We also investigated modification of the ethenyl group in the phenylethenesulfonamide moiety. ChemistryCharts 1 and 2 show the syntheses of alkenesulfonamide derivatives.The starting compound (3) was prepared according to the method reported by Burri and his coworkers.9) Nucleophilic substitution of the pyrimidine derivative 3 with (E)-alkenesulfonamide (4) resulted in the chloropyrimidine (5a-j, mx). The chloropyrimidine 5 was treated with sodium methoxide in N,N-dimethylformamide (DMF) or methanol to give the methoxy analogues (6a, c-j, m-x). Compound 3 was also treated with the methyl ester (4k) to give a mixture of the benzoic acid analogue (5l) and the methyl ester (5k). This mixture was treated with concentrated sulfuric acid in methanol to give 5k as a sole product. Treatment of 5k with sodium methoxide in methanol gave t...

In the present article we wish to report the discovery of a novel class of ET A -selective endothelin (ET) receptor antagonists through the modification of the ET A /ET B non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET A -selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET A -selectivity. [IC 50 ‫1.2؍‬ nM for ET A receptor, ET B /ET A ratio‫.]0021؍‬ After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR 2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

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Synthesis and Structure-Activity Relationships in a Series of Ethenesulfonamide Derivatives, a Novel Class of Endothelin ReceptorAntagonists.-Compound (IIb) is an ET A selective antagonist with an oral endothelin selective antagonistic activity in rats. -(HARADA, HI-

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