title: Structure-based design of aliskiren, a novel orally effective renin inhibitor.
abstract: 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.
authors.affiliation: Novartis Institute for Biomedical Research, Klybeckstrasse 220, CH-4002 Basel, Switzerland.
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Jürgen
authors.initials: J
authors.lastname: Maibaum
authors.forename: Joseph
authors.initials: J
authors.lastname: Rahuel
authors.forename: Markus G
authors.initials: MG
authors.lastname: Grütter
authors.forename: Nissim-Claude
authors.initials: NC
authors.lastname: Cohen
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rasetti
authors.forename: Heinrich
authors.initials: H
authors.lastname: Rüger
authors.forename: Richard
authors.initials: R
authors.lastname: Göschke
authors.forename: Stefan
authors.initials: S
authors.lastname: Stutz
authors.forename: Walter
authors.initials: W
authors.lastname: Fuhrer
authors.forename: Walter
authors.initials: W
authors.lastname: Schilling
authors.forename: Pascal
authors.initials: P
authors.lastname: Rigollier
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Frederic
authors.initials: F
authors.lastname: Cumin
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Baum
authors.forename: Christian R
authors.initials: CR
authors.lastname: Schnell
authors.forename: Peter
authors.initials: P
authors.lastname: Herold
authors.forename: Robert
authors.initials: R
authors.lastname: Mah
authors.forename: Chris
authors.initials: C
authors.lastname: Jensen
authors.forename: Eoin
authors.initials: E
authors.lastname: O'Brien
authors.forename: Alice
authors.initials: A
authors.lastname: Stanton
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bedigian
mesh_terms: 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
chemical_list: D000577:Amides; D005650:Fumarates; D010455:Peptides; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C446481:aliskiren