title: trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: prime site exploration using an amino linker.
abstract: Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2.
authors.affiliation: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland. Electronic address: edwige.lorthiois@novartis.com.
authors.forename: Edwige
authors.initials: E
authors.lastname: Lorthiois
authors.affiliation: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Cumin
authors.affiliation: Novartis Pharma AG, 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, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Sellner
authors.affiliation: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Ostermann
authors.affiliation: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Francotte
authors.affiliation: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Pharma AG, 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: D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D057055:Aspartic Acid Proteases; D011480:Protease Inhibitors; D011759:Pyrrolidines; D012083:Renin; D000092502:Renin Inhibitors; C032519:pyrrolidine
keywords: Direct renin inhibitor; Hypertension; Pyrrolidine; Structure guided drug design