Synthesis and renin inhibitory activity of novel angiotensinogen transition state analogues modified at the P(2)-histidine position

A Salimbeni; F Paleari; D Poma; M Criscuoli; C Scolastico

doi:10.1016/0223-5234(96)83977-8

Synthesis and renin inhibitory activity of novel angiotensinogen transition state analogues modified at the P(2)-histidine position

Eur J Med Chem. 1996;31(10):827-32. doi: 10.1016/0223-5234(96)83977-8.

Authors

A Salimbeni¹, F Paleari, D Poma, M Criscuoli, C Scolastico

Affiliation

¹ Medicinal Chemistry Department, Lusofarmaco(#), via Carnia 26, 20132 Milan, Italy.

PMID: 22026939
DOI: 10.1016/0223-5234(96)83977-8

Abstract

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.