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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Harada, H. et al.

Harada, Kazami, Watanuki, Tsuzuki, Sudoh, Fujimori, Tanaka, Tsukamoto, Yanagisawa,

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

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. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.[1]

References

Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists. Harada, H., Kazami, J., Watanuki, S., Tsuzuki, R., Sudoh, K., Fujimori, A., Tanaka, A., Tsukamoto, S., Yanagisawa, I. Chem. Pharm. Bull. (2001) [Pubmed]

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