Bosentan: structure-activity relationship + trial and error exploration-a carpet-like exploration process

Bosentan was developed by the Swiss company Exalon and was first approved by the US FDA in 2001.

Therefore, this article will briefly introduce Bosentan's research and development journey, and hope that more and more domestic companies will strengthen the research and development of this type of drug and give patients light and hope.

01

Discovery of lead compounds

Due to the lack of information on the three-dimensional structure of the endothelin receptor (ET), it is difficult for researchers to conduct rational molecular design.

02

Transformation of the 4-position substituent of the pyrimidine ring

After the NH methylation of the sulfonamide, the activity is significantly reduced, indicating the necessity of the hydrogen atom on the nitrogen for the activity.

03

Transformation of the 5-position substituent of the pyrimidine ring

Further replacing the trifluoromethyl group with a more lipophilic tert-butyl group, and at the same time changing the substituent on the 5-position benzene ring, in the synthesized compound, the activity of 3 is significantly improved, and animal experiments have shown that it has a better effect on hypertensive monkeys.

04

Conversion of the 2-position substituent of the pyrimidine ring

After introducing a benzene ring into the 2-position of the pyrimidine ring of compound 4, the activity was significantly increased (pA2=6.

05

Druggability research

The study of physical and chemical properties found that the solubility of derivative 6 in water was 0.

references

[1] Yanagisawa M, Kurihara H, KimuraS, et al.

[2] Burri K, Clozel M, Fischli W,et al.

und neue Sulfonamide.

[3] Neidhart W, Brau V, Bur D, etal.