The development of drugs that selectively block angiotensin receptors has resulted largely from a process of trialand-error medicinal chemistry on an early lead. The new generation of angiotensin antagonists or angiotensin mimetics are essentially devoid of side effects and are set to replace the angiotensin converting enzyme inhibitors for the treatment of cardiovascular diseases.

The model of angiotensin II (ANG II) developed in our laboratory using a combination of NMR, fluorescence data and molecular graphics [Matsoukas, J.M. et al., J. Biol. Chem., 269 (1994) 5303] served as a template for a systematic superimposition of potent AT1 receptor antagonists with ANG II. The key amino acids in this model, tyrosine, phenylalanine and histidine, form a charge-relay system. The studied ANG II AT1 receptor antagonists were found to accommodate this relay system. The proposed model offers a motivation to synthetic chemists to develop ANG II antagonists that differ from the losartan prototype structure but possess an enhanced biological profile.