Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl-3- [[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517).
Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25%) and, while subject to hepatic elimination in the monkey, were efficacious in this species.
Rosenberg
S H
SH
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, Illinois 60064.
Spina
K P
KP
Condon
S L
SL
Polakowski
J
J
Yao
Z
Z
Kovar
P
P
Stein
H H
HH
Cohen
J
J
Barlow
J L
JL
Klinghofer
V
V
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004386:Duodenum; D005289:Ferrets; D000882:Haplorhini; D006801:Humans; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000092502:Renin Inhibitors
D010879:Piperazines; D012083:Renin; D013844:Thiazoles; D000092502:Renin Inhibitors; C076903:zankiren hydrochloride