title: 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.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Göschke
authors.forename: Stefan
authors.initials: S
authors.lastname: Stutz
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rasetti
authors.forename: Nissim-Claude
authors.initials: NC
authors.lastname: Cohen
authors.forename: Joseph
authors.initials: J
authors.lastname: Rahuel
authors.forename: Pascal
authors.initials: P
authors.lastname: Rigollier
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Baum
authors.forename: Peter
authors.initials: P
authors.lastname: Forgiarini
authors.forename: Christian R
authors.initials: CR
authors.lastname: Schnell
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.forename: Markus G
authors.initials: MG
authors.lastname: Gruetter
authors.forename: Walter
authors.initials: W
authors.lastname: Fuhrer
authors.forename: Walter
authors.initials: W
authors.lastname: Schilling
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cumin
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Jürgen
authors.initials: J
authors.lastname: Maibaum
mesh_terms: 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