New renin inhibitors containing aliphatic or aromatic amides at the C-terminus

Five renin inhibitors, Iva-Pro-Phe(4-OMe)-MeLeu-Sta-eAhx-IAA (18), Iva-eAhx-Phe(4-OMe)-MeLeu-Sta-eAhx-IAA (23), H-eAhx-Phe(4-OMe)-His-Sta-eAhx-FBZA (36), H-eAhx-Phe(4-OMe)-His-Sta-eAhx-MBZA (45), and H-Phe(4-OMe)-His-Sta-eAhx-FBZA (48) have been synthesized in search of structures of improved biological properties. All synthesized inhibitors were resistant to chymotrypsin activity. Inhibitors 18 and 23 were insoluble in buffers, pH 7.4 and 2.0, 36,45 and 48 were very good soluble soluble in buffer pH 2.0 and poorly in buffer pH 7.4. Experimentally determined 1-octanol/pH 7.4 buffer partition coeficient (log P) of 36, 45 and 48 were above 1. Log P values of 18,23,36,45 and 48 were 6.57,6.91,2.48,2.09 and 2.00 respectively. The inhibitory potency in vitro of 18,23,36,45 and 48 expressed as IC 50 was 7.5.10 -5 , 5.0.10 -6 , 7.5.10 -3 , 1.0.10 -4 and 2.5.10 -5 M/l respectively