Structure-based design of aliskiren, a novel orally effective renin inhibitor.
Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.
Wood
Jeanette M
JM
Novartis Institute for Biomedical Research, Klybeckstrasse 220, CH-4002 Basel, Switzerland.
Maibaum
Jürgen
J
Rahuel
Joseph
J
Grütter
Markus G
MG
Cohen
Nissim-Claude
NC
Rasetti
Vittorio
V
Rüger
Heinrich
H
Göschke
Richard
R
Stutz
Stefan
S
Fuhrer
Walter
W
Schilling
Walter
W
Rigollier
Pascal
P
Yamaguchi
Yasuchika
Y
Cumin
Frederic
F
Baum
Hans-Peter
HP
Schnell
Christian R
CR
Herold
Peter
P
Mah
Robert
R
Jensen
Chris
C
O'Brien
Eoin
E
Stanton
Alice
A
Bedigian
Martin P
MP
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides; D000818:Animals; D001794:Blood Pressure; D018360:Crystallography, X-Ray; D015195:Drug Design; D005650:Fumarates / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D008875:Middle Aged; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D012083:Renin / Q000097:blood / Q000737:chemistry; D012084:Renin-Angiotensin System / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors; D000092502:Renin Inhibitors
D000577:Amides; D005650:Fumarates; D010455:Peptides; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C446481:aliskiren