Pratosartan

A series of novel 2'-tetrazole and 2'-carboxy-biphenylylmethyl-pyrrolidine derivatives were designed and evaluated as Ang II AT₁ receptor antagonists (angiotensin AT1 receptor antagonists).The compare/fit scores of these mols. were determined using an Ang II AT₁ receptor antagonist hypothesis constructed from known antagonists using CATALYST/DS modules and demonstrated significantly high simulated fit values.These hit mols. were subsequently synthesized and their in vivo antihypotensive and antihypertensive activities evaluated in normotensive cats, normotensive rats and hypertensive rats.Several compounds showed lower or similar levels of activity to the reference compound losartan.In contrast, the activity of several compounds was 1.5-fold and 2-fold higher than losartan.Furthermore, the LD₅₀ value for one compound was determined to be 117 μg/Kg.The synthesis of the target compounds was achieved using 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-(triphenylmethyl)-2H-tetrazole, 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile, 1-acetyl-5-[(4-methoxyphenyl)methyl]-4-oxo-3-pyrrolidinecarboxylic acid ester as starting materials.The title compounds thus formed included [[[(methoxyphenyl)methyl]pyrrolidinyl]methyl]biphenylcarboxylic acid derivatives and tetrazole analogs, nitrile analogs.