Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.
A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.
Patt
W C
WC
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105.
Hamilton
H W
HW
Taylor
M D
MD
Ryan
M J
MJ
Taylor
D G
DG
Connolly
C J
CJ
Doherty
A M
AM
Klutchko
S R
SR
Sircar
I
I
Steinbaugh
B A
BA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004795:Enzyme Stability; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D012083:Renin / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D000092502:Renin Inhibitors
D002402:Cathepsin D; D004791:Enzyme Inhibitors; D012083:Renin; D013844:Thiazoles; D000092502:Renin Inhibitors