(Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme. 2. Terminal amino acid analogues of (S)-1-[6-amino-2 [[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline.
Analogues of (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl)phosphinyl] oxy]-1-oxohexyl]-L-proline (1, SQ 29,852) in which the terminal proline residue has been replaced by a variety of substituted and heteroatom-substituted prolines, N-arylglycines, N-cycloalkylglycines, and bicyclic amino acids have been synthesized and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.
Karanewsky
D S
DS
Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Badia
M C
MC
Cushman
D W
DW
DeForrest
J M
JM
Dejneka
T
T
Lee
V G
VG
Loots
M J
MJ
Petrillo
E W
EW
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D009943:Organophosphorus Compounds; C063796:2,3-dihydro-1-(6-amino-2-((hydroxy-(4-phenylbutyl)phosphinyl)oxy)-1-oxohexyl)-1H-indole-2-carboxylic acid; D011392:Proline; C054518:ceronapril