Nonpeptide renin inhibitors employing a novel 3-aza(or oxa)-2,4-dialkyl glutaric acid moiety as a P2/P3 amide bond replacement.
A new series of renin inhibitors has been developed. The inhibitors feature a novel replacement for the P2/P3 dipeptide moiety normally associated with renin inhibitors. The dipeptide replacement was a (2S,4S)-3-aza(or oxa)-2,4-dialkylglutaric acid amide. Extensive structure-activity relationship studies determined that optimum potency was achieved when inhibitors employed a benzyl and butyl group at the C(4) and C(2) carbon position, respectively. In addition, maximum in vitro potency was obtained when the N-terminus was functionalized by incorporating a 4-(1,3-dioxabutyl)piperidine amide. SAR data suggested that the 1,3-dioxabutyl group (methoxymethyl ether) interacted by hydrogen bonding to groups in the S4 domain of renin. This hypothesis was strengthened when a 4-butylpiperidine amide was substituted and inhibitor potency decreased dramatically. Inhibitors employing this novel dipeptide mimic were prepared by coupling the glutaric acid amides with either the transition-state mimic (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6- methylheptane (18) or the hydroxyethylene dipeptide isostere. The glutaric acid amides were prepared by two general procedures. The first procedure involved the reductive amination of alpha-amino acid esters with alpha-keto esters. The second procedure involved the displacement reaction of alpha-bromo esters or acids with alpha-amino acid amides.
Baker
W R
WR
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Fung
A K
AK
Kleinert
H D
HD
Stein
H H
HH
Plattner
J J
JJ
Armiger
Y L
YL
Condon
S L
SL
Cohen
J
J
Egan
D A
DA
Barlow
J L
JL
D000577:Amides / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005977:Glutarates / Q000737:chemistry* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008969:Molecular Sequence Data; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D004151:Dipeptides; D004656:Enalapril; D004791:Enzyme Inhibitors; D005977:Glutarates; D012083:Renin; D000092502:Renin Inhibitors; C056622:enalkiren