The role of position 4 in angiotensin II antagonism: a structure-activity study.

A number of [Sar1,(pX)Phe4]-ANG II and [Sar1,(pX)Phe4,Ile8]-ANG II analogues were prepared. A good correlation between pX structure in [Sar1,(pX)Phe4]-ANG II and antagonist activity could not be found. However, the data suggest a general trend: Position 4 para substituents that are hydrophilic and capable of donating a hydrogen atom in a hydrogen bond promote agonist activity, while para substituents that are hydrophobic and incapable of donating a hydrogen atom promote antagonist activity. These properties were found to be optimal in the p-chloro substituent. The resulting analogue [Sar1,(pCl)Phe4]-ANG II is a potent ANG II antagonist in vivo. The pX substituents that promote antagonist activity in the [Sar1,(pX)Phe4]-ANG II series were unfavorable in [Sar1,(pX)Phe4,Ile8]-ANG II analogues. ANG II analogues that are antagonists by virtue of an alteration in position 8 require a position 4 agonist side chain. Concurrent modifications of positions 4 and 8 do not give rise to potent antagonists with reduced partial agonist activity.