Synthesis and ACE inhibitory activity of the stereoisomers of perindopril (S 9490) and perindoprilate (S 9780).
Perindopril, a powerful ACE inhibitor contains 5 chiral carbons, thus there is the possibility of 2(5) = 32 stereoisomers for the general structure 1. These 32 stereoisomers were synthesized by cross-coupling the 8 stereoisomers of perhydroindole 2-carboxylic acid benzylester with the 4 stereoisomers of 2-(1-carbethoxybutylamino) propionic acid 4, then hydrogenating the resulting benzylesters. Each stereoisomer of perindopril furnished by saponification the corresponding diacid stereoisomer 2 of perindoprilate which is the active form of perindopril. For each of the 32 stereoisomers 2 the in vitro ACE inhibitory potency (IC50) was determined. Four of them, including perindoprilate, had activities in the nanomolar range, and four more were ca. 10 x less active. The four acid esters 1 corresponding respectively to the four most active diacids 2 in vitro were studied (1 mg/kg via the oral route) for their in vivo activity in dogs. It could be concluded that p.o. absorption of the active acid esters 1 and their activation to the active diacid 2 depended only on the chiralities of the two ring junction carbons of the perhydroindole ring.
Vincent
M
M
Institut de Recherches Servier-11, Suresnes, France.
Marchand
B
B
Rémond
G
G
Jaguelin-Guinamant
S
S
Damien
G
G
Portevin
B
B
Baumal
J Y
JY
Volland
J P
JP
Bouchet
J P
JP
Lambert
P H
PH
D000284:Administration, Oral; D000803:Angiotensin I / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D020913:Perindopril; D013237:Stereoisomerism; D013379:Substrate Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C053500:perindoprilat; D000803:Angiotensin I; D020913:Perindopril