Synthesis and in vitro activities of new non-peptidic APA inhibitors.
Aminopeptidase A (APA) is involved in the maturation of angiotensin III, a peptide which seems to be implicated in blood pressure regulation at the brain level. Therefore APA inhibitors are potential new antihypertensive agents with possible novel applications. With the aim of enhancing the bioavailability and potency of EC 33, the APA inhibitor (Ki = 300 nM) initially used in the earlier studies, we have synthesized new non-peptidic inhibitors able to interact with the S1 and S'1 subsites of the targeted enzyme. Compound 10a, (3S,4S)-3-amino-4-mercapto-6-phenyl-hexane-1-sulfonic acid was obtained using an asymmetric synthesis. Inhibitor 10a exhibits a Ki value of 30 nm.
Inguimbert
N
N
Laboratoire de Pharmacologie Chimique et Génétique, Université René Descartes Paris V, UFR des Sciences Pharmaceutiques et Biologiques, INSERM U 640, CNRS UMR 8151, 4, avenue de l'observatoire, 75270 Paris Cedex 06, France.
Coric
P
P
Dhotel
H
H
Bonnard
E
E
Llorens-Cortes
C
C
Mota
N
N
Fournié-Zaluski
M-C
MC
Roques
B-P
BP
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D043384:Glutamyl Aminopeptidase / Q000037:antagonists & inhibitors*; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C502311:(3S,4S)-3-amino-4-mercapto-6-phenyl-hexane-1-sulfonic acid; D000959:Antihypertensive Agents; C101968:EC 33; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D013451:Sulfonic Acids; D043384:Glutamyl Aminopeptidase