METABOLITES OF THE ANGIOTENSIN-II ANTAGONIST TASOSARTAN - THE IMPORTANCE OF A 2ND ACIDIC GROUP

Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). O f particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-ac tivity relationship of other angiotensin II antagonist series, a secon d acidic group can improve receptor binding activity but decrease in v ivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to t he excellent profile of the compound. A molecular modeling study provi des a rationale for the role of the enol group of 8 in AT(1) receptor binding.