title: Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.
abstract: A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Takeru
authors: T
authors: Ehara
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Osamu
authors: O
authors: Irie
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Takatoshi
authors: T
authors: Kosaka
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Takanori
authors: T
authors: Kanazawa
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Werner
authors: W
authors: Breitenstein
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Philipp
authors: P
authors: Grosche
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Nils
authors: N
authors: Ostermann
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Masaki
authors: M
authors: Suzuki
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Shimpei
authors: S
authors: Kawakami
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Kazuhide
authors: K
authors: Konishi
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Yuko
authors: Y
authors: Hitomi
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Atsushi
authors: A
authors: Toyao
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Hiroki
authors: H
authors: Gunji
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Frederic
authors: F
authors: Cumin
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Nikolaus
authors: N
authors: Schiering
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Trixie
authors: T
authors: Wagner
authors: Novartis Pharmaceuticals Corp., Institutes for BioMedical Research , East Hanover, New Jersey 07936, United States.
authors: Dean F
authors: DF
authors: Rigel
authors: Novartis Pharmaceuticals Corp., Institutes for BioMedical Research , East Hanover, New Jersey 07936, United States.
authors: Randy L
authors: RL
authors: Webb
authors: Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors: Jürgen
authors: J
authors: Maibaum
authors: Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.
authors: Fumiaki
authors: F
authors: Yokokawa
keywords: 3,5-piperidines; Renin inhibitor; aspartic protease; structure-based design