title: Synthesis and inhibitory activities against aminopeptidase B and enkephalin-degrading enzymes of ketomethylene dipeptide analogues of arphamenines.
abstract: 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.
authors.affiliation: Instituto de Química Médica, C.S.I.C., Madrid, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: García-López
authors.forename: R
authors.initials: R
authors.lastname: González-Muñiz
authors.forename: J R
authors.initials: JR
authors.lastname: Hartoa
authors.forename: I
authors.initials: I
authors.lastname: Gómez-Monterrey
authors.forename: C
authors.initials: C
authors.lastname: Pérez
authors.forename: M L
authors.initials: ML
authors.lastname: De Ceballos
authors.forename: E
authors.initials: E
authors.lastname: López
authors.forename: J
authors.initials: J
authors.lastname: Del Río
mesh_terms: 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
chemical_list: D006146:Guanidines; D007659:Ketones; C040038:arphamenine A; D000626:Aminopeptidases; C019721:aminopeptidase B; D015260:Neprilysin