A PRACTICAL SYNTHESIS OF THE [(2R)-3-(MORPHOLINOCARBONYL)-2-(1-NAPHTHYL-METHYL)PROPIONYL]-L-HISTIDINE MOIETY (P4-P2) IN RENIN INHIBITORS

A large number of renin inhibitors have been investigated as therapeutic agents of hypertension.1,2 The peptide inhibitors derived from renin substrate angiotensi-nogen have been considered to be unsuitable as drugs for oral administration due to proteolytic degradation by chymotrypsin, especially at the Phe-His amide bond (P3-P2)3 of the inhibitors.4 Recently, we have reported a novel class of low molecular weight renin inhibitor such as 1 which was stabilized against proteases by incorporating (-)-3-(morpholinocarbonyl)-2-(l-naphthylmethyl)-propionic acid [(-)-2] with a retro-inverso amide bond as the P4-P3 moiety.1 In addition, the analysis of in-hibitor-renin interaction5 showed that the /3-carbonyl group of (-)-2 was at a suitable position to accept a hydrogen bond from the side chain OH of Ser-230 in human renin, the naphthyl group of P3was accommodated in the hydrophobic subsite S3of renin, and the imidazole of P2His was hydrogen bonded to the side chain OH of Ser-233. © 1990, American Chemical Society. All rights reserved.