Literature DB >> 25050166

Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.

Takeru Ehara1, Osamu Irie1, Takatoshi Kosaka1, Takanori Kanazawa1, Werner Breitenstein2, Philipp Grosche2, Nils Ostermann2, Masaki Suzuki1, Shimpei Kawakami1, Kazuhide Konishi1, Yuko Hitomi1, Atsushi Toyao1, Hiroki Gunji1, Frederic Cumin2, Nikolaus Schiering2, Trixie Wagner2, Dean F Rigel3, Randy L Webb3, Jürgen Maibaum2, Fumiaki Yokokawa1.   

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.

Entities:  

Keywords:  3,5-piperidines; Renin inhibitor; aspartic protease; structure-based design

Year:  2014        PMID： 25050166      PMCID： PMC4094259          DOI： 10.1021/ml500137b

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  17 in total

Review 1.  Direct renin inhibitors as a new therapy for hypertension.

Authors:  Randy L Webb; Nikolaus Schiering; Richard Sedrani; Jürgen Maibaum
Journal:  J Med Chem       Date:  2010-11-11       Impact factor: 7.446

2.  Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets.

Authors:  Jürgen Maibaum; Stefan Stutz; Richard Göschke; Pascal Rigollier; Yasuchika Yamaguchi; Frédéric Cumin; Joseph Rahuel; Hans-Peter Baum; Nissim-Claude Cohen; Christian R Schnell; Walter Fuhrer; Markus G Gruetter; Walter Schilling; Jeanette M Wood
Journal:  J Med Chem       Date:  2007-09-08       Impact factor: 7.446

3.  Ketopiperazine-based renin inhibitors: optimization of the "C" ring.

Authors:  Daniel D Holsworth; Cuiman Cai; Xue-Min Cheng; Wayne L Cody; Dennis M Downing; Noe Erasga; Chitase Lee; Noel A Powell; Jeremy J Edmunds; Michael Stier; Mehran Jalaie; Erli Zhang; Pat McConnell; Michael J Ryan; John Bryant; Tingsheng Li; Aparna Kasani; Eric Hall; Rajendra Subedi; Mohammad Rahim; Samarendra Maiti
Journal:  Bioorg Med Chem Lett       Date:  2006-02-15       Impact factor: 2.823

4.  Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct.

Authors:  K E Zhang; P H Kari; M R Davis; G Doss; T A Baillie; K P Vyas
Journal:  Drug Metab Dispos       Date:  2000-06       Impact factor: 3.922

Review 5.  Recent progress on the discovery of non-peptidic direct renin inhibitors for the clinical management of hypertension.

Authors:  Fumiaki Yokokawa
Journal:  Expert Opin Drug Discov       Date:  2013-04-18       Impact factor: 6.098

6.  Global burden of hypertension: analysis of worldwide data.

Authors:  Patricia M Kearney; Megan Whelton; Kristi Reynolds; Paul Muntner; Paul K Whelton; Jiang He
Journal:  Lancet       Date:  2005 Jan 15-21       Impact factor: 79.321

7.  Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of tertiary alcohol-bearing piperidines.

Authors:  Austin Chen; Elizabeth Cauchon; Amandine Chefson; Sarah Dolman; Yves Ducharme; Daniel Dubé; Jean-Pierre Falgueyret; Pierre-André Fournier; Sébastien Gagné; Michel Gallant; Erich Grimm; Yongxin Han; Robert Houle; Jing-Qi Huang; Gregory Hughes; Hélène Jûteau; Patrick Lacombe; Sophie Lauzon; Jean-François Lévesque; Susana Liu; Dwight Macdonald; Bruce Mackay; Dan McKay; M David Percival; René St-Jacques; Sylvie Toulmond
Journal:  Bioorg Med Chem Lett       Date:  2011-05-14       Impact factor: 2.823

8.  Chemoenzymatic synthesis of isogalactofagomine.

Authors:  X Liang; A Lohse; M Bols
Journal:  J Org Chem       Date:  2000-11-03       Impact factor: 4.354

9.  The discovery of novel potent trans-3,4-disubstituted pyrrolidine inhibitors of the human aspartic protease renin from in silico three-dimensional (3D) pharmacophore searches.

Authors:  Edwige Lorthiois; Werner Breitenstein; Frederic Cumin; Claus Ehrhardt; Eric Francotte; Edgar Jacoby; Nils Ostermann; Holger Sellner; Takatoshi Kosaka; Randy L Webb; Dean F Rigel; Ulrich Hassiepen; Paul Richert; Trixie Wagner; Jürgen Maibaum
Journal:  J Med Chem       Date:  2013-03-15       Impact factor: 7.446

10.  Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.

Authors:  Olivier Bezençon; Daniel Bur; Thomas Weller; Sylvia Richard-Bildstein; Lubos Remen; Thierry Sifferlen; Olivier Corminboeuf; Corinna Grisostomi; Christoph Boss; Lars Prade; Stéphane Delahaye; Alexander Treiber; Panja Strickner; Christoph Binkert; Patrick Hess; Beat Steiner; Walter Fischli
Journal:  J Med Chem       Date:  2009-06-25       Impact factor: 7.446
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  2 in total

1.  Discovery of 18F-JK-PSMA-7, a PET Probe for the Detection of Small PSMA-Positive Lesions.

Authors:  Boris D Zlatopolskiy; Heike Endepols; Philipp Krapf; Mehrab Guliyev; Elizaveta A Urusova; Raphael Richarz; Melanie Hohberg; Markus Dietlein; Alexander Drzezga; Bernd Neumaier
Journal:  J Nucl Med       Date:  2018-11-02       Impact factor: 10.057

2.  Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.

Authors:  Yasuhiro Imaeda; Hidekazu Tokuhara; Yoshiyuki Fukase; Ray Kanagawa; Yumiko Kajimoto; Keiji Kusumoto; Mitsuyo Kondo; Gyorgy Snell; Craig A Behnke; Takanobu Kuroita
Journal:  ACS Med Chem Lett       Date:  2016-09-12       Impact factor: 4.345
  2 in total

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