Discovery of novel non-peptidic ketopiperazine-based renin inhibitors.
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).
Holsworth
Daniel D
DD
Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. daniel.holsworth@pfizer.com <daniel.holsworth@pfizer.com>
Powell
Noel A
NA
Downing
Dennis M
DM
Cai
Cuiman
C
Cody
Wayne L
WL
Ryan
J Michael
JM
Ostroski
Robert
R
Jalaie
Mehran
M
Bryant
John W
JW
Edmunds
Jeremy J
JJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D004791:Enzyme Inhibitors; D010879:Piperazines; D000092502:Renin Inhibitors