SYNTHESIS AND RENIN INHIBITORY ACTIVITY OF NOVEL ANGIOTENSINOGEN TRANSITION-STATE ANALOGS MODIFIED AT THE P-2-HISTIDINE POSITION

With the aim of finding new renin inhibitors with improved bioavailabi lity properties, two angiotensinogen transition state analogues 1a and 1b, containing a novel unnatural amino acid at the P-2 position, name ly the (2R,3S)- and -2-amino-3-(1,3-dithiolan-2-yl)-3-hydroxypropanoic acid (ADHPA), have been synthesized and tested for human renin inhibi tory activity and for chemical and enzymatic stability. Only compound 1a (the S-isomer) possessed a significant activity, which was lower th an that of the corresponding histidyl derivative KRI-1314, and combine d with a low stability to the gut enzyme chymotrypsin.