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

• Published in: Journal of medicinal chemistry Vol. 50; no. 20; pp. 4818 - 4831
• Main Authors: Göschke, Richard, Stutz, Stefan, Rasetti, Vittorio, Cohen, Nissim-Claude, Rahuel, Joseph, Rigollier, Pascal, Baum, Hans-Peter, Forgiarini, Peter, Schnell, Christian R, Wagner, Trixie, Gruetter, Markus G, Fuhrer, Walter, Schilling, Walter, Cumin, Frédéric, Wood, Jeanette M, Maibaum, Jürgen
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.10.2007; Amer Chemical Soc
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Anisoles - chemical synthesis; Anisoles - chemistry; Anisoles - pharmacology; Antihypertensive agents; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Biological and medical sciences; Biological Availability; Blood Pressure - drug effects; Callithrix; Caprylates - chemical synthesis; Caprylates - chemistry; Caprylates - pharmacology; Cardiovascular system; Chemistry, Medicinal; Crystallography, X-Ray; Heart Rate - drug effects; Humans; Kinetics; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Mimicry; Molecular Structure; Peptides - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Renin - antagonists & inhibitors; Renin - blood; Science & Technology; Stereoisomerism; Structure-Activity Relationship; COMPLEX; DESIGN; PLASMA; HYDROXYETHYLENE DIPEPTIDE ISOSTERES; CRYSTAL-STRUCTURES; ALISKIREN; BLOOD-PRESSURE; DISCOVERY; BIOAVAILABILITY; ENALKIREN; Hydroxyamide; Monkey; Non peptide compound; Modeling; Renin; Structure activity relation; Molecular model; Primates; Aspartic endopeptidases; Chemical synthesis; Human; Aminoalcohol; Ether; Enzyme; Aliphatic compound; Peptidomimetic compound; Benzene derivatives; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Transition state; Hydrolases; Antihypertensive agent; Carboxamide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070314y

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.