Synthesis and inhibitory activities against aminopeptidase B and enkephalin-degrading enzymes of ketomethylene dipeptide analogues of arphamenines.
Three ketomethylene pseudodideptide analogues [(S)Lys psi(COCH2)(R and S)Phe (14 or 15 and 15 or 14) and (S)Lys psi(COCH2)(xi Trp (19)] of natural arphamenine A [(S)Arg psi(COCH2(R,S)Phe (1)] were easily prepared by a route involving two successive main reactions: a malonic ester alkylation with Z-protected lysine iodomethyl ketone and the introduction of a benzyl or (indol-3-yl)methyl moiety in position 2 of the resulting 4-ketodiester. The isomer of 1 with reversed sequence, (S)Phe psi(COCH2)(R,S)Arg (22) was synthesized by guanidylation and subsequent deprotection of Z-(S)Phe psi(COCH2)(R,S)Orn. The inhibitory effects of compounds 14, 15, 19, and 22, and the related ketomethylene dipeptides (S)Ala psi(COCH2)(R,S)Phe (3), (S)Phe psi(COCH2)(R,S)X [X = Ala (4), Orn (5)] and (S)Trp psi(COCH2)(R,S)Y [Y = Orn (6), Lys (7), Arg (8)] on aminopeptidase B (AP-B), and enkephalin-degrading enzymes [aminopeptidase N (APN) and neutral endopeptidase (NEP)] were compared with that of the model compound 1.
García-López
M T
MT
Instituto de Química Médica, C.S.I.C., Madrid, Spain.
González-Muñiz
R
R
Hartoa
J R
JR
Gómez-Monterrey
I
I
Pérez
C
C
De Ceballos
M L
ML
López
E
E
Del Río
J
J
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats
D006146:Guanidines; D007659:Ketones; C040038:arphamenine A; D000626:Aminopeptidases; C019721:aminopeptidase B; D015260:Neprilysin