Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets.
Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension.
Maibaum
Jürgen
J
Novartis Institutes for BioMedical Research, NOVARTIS Pharma AG, WKL-136.683, CH-4002 Basel, Switzerland. juergen_klaus.maibaum@novartis.com
Stutz
Stefan
S
Göschke
Richard
R
Rigollier
Pascal
P
Yamaguchi
Yasuchika
Y
Cumin
Frédéric
F
Rahuel
Joseph
J
Baum
Hans-Peter
HP
Cohen
Nissim-Claude
NC
Schnell
Christian R
CR
Fuhrer
Walter
W
Gruetter
Markus G
MG
Schilling
Walter
W
Wood
Jeanette M
JM
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002144:Callithrix; D002210:Caprylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005650:Fumarates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012083:Renin / Q000097:blood; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors