(PHOSPHINYLOXY)ACYL AMINO-ACID INHIBITORS OF ANGIOTENSIN CONVERTING ENZYME .2. TERMINAL AMINO-ACID-ANALOGS OF (S)-1-[6-AMINO-2-[[HYDROXY(4-PHENYLBUTYL)PHOSPHINYL]OXY]-1-OXOHEXYL]-L-PROLINE

Analogues of (S)-l-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-l-oxohexyl]-L-proline (1, SQ 29,852) in which the terminal proline residue has been replaced by a variety of substituted and heteroatom-substituted prolines, N-arylglycines, N-cycloalkylglycines, and bicyclic amino acids have been synthesized and evaluated as inhibitors of angiotensin converting enzyme in vitro and in vivo. In general, the addition of lipophilic substituents to the 4-position of proline of the parent phosphonate 1 resulted in substantial increases in in vitro activity. The largest improvements were observed in the case of cis-benzyl (36-fold) and dithioketal (24-fold) analogues 2r and 2x, respectively. These enhancements of in vitro activity were accompanied by modest increases (2-3.5-fold) in in vivo (iv) activity. Among the various terminal amino acid replacements examined in this study, the indoline-based analogue 2i was by far the most potent compound on iv administration in the normotensive rat. © 1990, American Chemical Society. All rights reserved.