Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types

Abstract

The synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.

Pharmacology and Clinical Use of the New ACE‐Inhibitor Moexipril

“…L 29) or [3S-[2[R*(R*) ],3R*] 1-2-[2-[ [ l -(ethoxycarbonyl)-3-phenylpropyl]amino]-1 -oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride was synthesized by Hoefle and Klutchko (15,19). Moexipril hydrochloride is a white powder with a molecular weight of 535.04 and a melting point of 155°C to 160°C.…”

Nouvelle voie de synthèse d'isoindolones et d'isoquinoléines par condensation d'iminophosphoranes avec l'ortho-phtalaldéhyde: réactions, mécanismes et étude structurale

“…Enfin, les quatre synthkses d'isoquinoltines acyltes en position 3 reportees dans la litttrature cornportent de nombreuses ttapes et la prtparation prtalable d'isoquinoltines substituCes en position 3 par un reste de type halogkne (22,23), mtthyle (24) ou carboxylate d'tthyle (25). Enfin les multiples possibilitCs synthttiques au depart des cttones rendent notre mtthode particulierement inttressante pour acceder 2 la famille des isoquinoltines substitutes en position 3, composts qui ont Ct C ttudiCs en tant qu'inhibiteurs d'enzymes (26), intermtdiaires de synthbe (27), ou modkles biologiques (25). Ajoutons egalement que certains mttabolites fongiques appartiennent cette classe d'htttrocycles (28).…”

Applications and Modifications of 1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acid (Tic) in Peptides and Peptidomimetics Design and Discovery

“…A strategy which has now been applied successfully in several cases is replacing the proline residue with Tic residue [42][43][44][45][46]. In 1983, Hayashi and co-workers reported that the in vitro ACE inhibitory activity of compound 55 was more potent than its precursor captopril, and the in vivo activity and hypotensive effects of compound 55 were also comparable to captopril [42].…”

“…The most successful case was the optimization of enalapril, which led to another more potent approved drug quinapril 57, Fig. (11) [46]. Generally, hydrophobic compounds are more potent.…”