Synthesis and renin inhibitory activity of novel angiotensinogen transition state analogues modified at the P(2)-histidine position.
With the aim of finding new renin inhibitors with improved bioavailability properties, two angiotensinogen transition state analogues 1a and 1b, containing a novel unnatural amino acid at the P(2) position, namely the (2R,3S)- and (2S,3S)-2-amino-3-(1,3-dithiolan-2-yl)-3-hydroxypropanoic acid (ADHPA), have been synthesized and tested for human renin inhibitory activity and for chemical and enzymatic stability. Only compound 1a (the S-isomer) possessed a significant activity, which was lower than that of the corresponding histidyl derivative KRI-1314, and combined with a low stability to the gut enzyme chymotrypsin.
Medicinal Chemistry Department, Lusofarmaco(#), via Carnia 26, 20132 Milan, Italy.
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Salimbeni
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Paleari
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Poma
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Criscuoli
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