Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin.
The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.
Göschke
Richard
R
Novartis Institutes for BioMedical Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland.
Stutz
Stefan
S
Rasetti
Vittorio
V
Cohen
Nissim-Claude
NC
Rahuel
Joseph
J
Rigollier
Pascal
P
Baum
Hans-Peter
HP
Forgiarini
Peter
P
Schnell
Christian R
CR
Wagner
Trixie
T
Gruetter
Markus G
MG
Fuhrer
Walter
W
Schilling
Walter
W
Cumin
Frédéric
F
Wood
Jeanette M
JM
Maibaum
Jürgen
J
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002144:Callithrix; D002210:Caprylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D012083:Renin / Q000097:blood; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors