title: trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: prime site exploration using an oxygen linker.
abstract: Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing.
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland. Electronic address: holger.sellner@novartis.com.
authors.forename: Holger
authors.initials: H
authors.lastname: Sellner
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Cottens
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cumin
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Claus
authors.initials: C
authors.lastname: Ehrhardt
authors.affiliation: Novartis Institutes for BioMedical Research, Okhubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Edwige
authors.initials: E
authors.lastname: Lorthiois
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Ostermann
authors.affiliation: Novartis Pharmaceuticals Corp., Novartis Institutes for BioMedical Research, East Hanover, NJ, United States.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Webb
authors.affiliation: Novartis Pharmaceuticals Corp., Novartis Institutes for BioMedical Research, East Hanover, NJ, United States.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland. Electronic address: juergen_klaus.maibaum@novartis.com.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Maibaum
mesh_terms: D000818:Animals; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D006860:Hydrogen Bonding; D006973:Hypertension / Q000188:drug therapy; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D010100:Oxygen / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D057055:Aspartic Acid Proteases; D010100:Oxygen; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012083:Renin; D000092502:Renin Inhibitors; C032519:pyrrolidine
keywords: Direct renin inhibitor; In vivo potency; Pyrrolidine; Structure guided drug design