Literature DB >> 24900262

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.

Lanqi Jia1, Robert D Simpson1, Jing Yuan1, Zhenrong Xu1, Wei Zhao1, Salvacion Cacatian1, Colin M Tice1, Joan Guo1, Alexey Ishchenko1, Suresh B Singh1, Zhongren Wu1, Brian M McKeever1, Yuri Bukhtiyarov1, Judith A Johnson1, Christopher P Doe2, Richard K Harrison1, Gerard M McGeehan1, Lawrence W Dillard1, John J Baldwin1, David A Claremon1.   

Abstract

Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Entities:  

Keywords:  Renin; aspartyl protease; hypertension; structure-based drug design

Year:  2011        PMID： 24900262      PMCID： PMC4018089          DOI： 10.1021/ml200137x

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


  22 in total

1.  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

Review 2.  Chronic kidney disease: definition and staging--an orthodox view.

Authors:  C G Winearls
Journal:  Clin Med (Lond)       Date:  2009-12       Impact factor: 2.659

3.  Optimization of orally bioavailable alkyl amine renin inhibitors.

Authors:  Zhenrong Xu; Salvacion Cacatian; Jing Yuan; Robert D Simpson; Lanqi Jia; Wei Zhao; Colin M Tice; Patrick T Flaherty; Joan Guo; Alexey Ishchenko; Suresh B Singh; Zhongren Wu; Brian M McKeever; Boyd B Scott; Yuri Bukhtiyarov; Jennifer Berbaum; Jennifer Mason; Reshma Panemangalore; Maria Grazia Cappiello; Ross Bentley; Christopher P Doe; Richard K Harrison; Gerard M McGeehan; Lawrence W Dillard; John J Baldwin; David A Claremon
Journal:  Bioorg Med Chem Lett       Date:  2009-12-01       Impact factor: 2.823

Review 4.  Inhibitors of renin as potential therapeutic agents.

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Journal:  J Enzyme Inhib       Date:  1987

5.  Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study.

Authors:  Austin Chen; Daniel Dubé; Laurence Dubé; Sébastien Gagné; Michel Gallant; Mireille Gaudreault; Erich Grimm; Robert Houle; Patrick Lacombe; Sébastien Laliberté; Suzanna Liu; Dwight MacDonald; Bruce Mackay; David Martin; Dan McKay; David Powell; Jean-François Lévesque
Journal:  Bioorg Med Chem Lett       Date:  2010-07-11       Impact factor: 2.823

Review 6.  Renin inhibitors.

Authors:  S H Rosenberg
Journal:  Prog Med Chem       Date:  1995

7.  Expression of components of the RAS during prolonged blockade at different levels in primates.

Authors:  N J Samani; F Cumin; M Kelly; J M Wood
Journal:  Am J Physiol       Date:  1994-10

Review 8.  The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease.

Authors:  Giuseppe Remuzzi; Norberto Perico; Manuel Macia; Piero Ruggenenti
Journal:  Kidney Int Suppl       Date:  2005-12       Impact factor: 10.545

9.  On the size of the active site in proteases. I. Papain.

Authors:  I Schechter; A Berger
Journal:  Biochem Biophys Res Commun       Date:  1967-04-20       Impact factor: 3.575

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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  3 in total

1.  Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.

Authors:  Yuji Nakamura; Teppei Fujimoto; Yasuyuki Ogawa; Chie Sugita; Shojiro Miyazaki; Kazuhiko Tamaki; Mizuki Takahashi; Yumi Matsui; Takahiro Nagayama; Kenichi Manabe; Makoto Mizuno; Noriko Masubuchi; Katsuyoshi Chiba; Takahide Nishi
Journal:  ACS Med Chem Lett       Date:  2012-08-18       Impact factor: 4.345

2.  Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.

Authors:  Ian S Cloudsdale; John K Dickson; Thomas E Barta; Brian S Grella; Emilie D Smith; John L Kulp; Frank Guarnieri; John L Kulp
Journal:  Bioorg Med Chem       Date:  2017-05-19       Impact factor: 3.641

3.  Rapid functionalization of multiple C-H bonds in unprotected alicyclic amines.

Authors:  Weijie Chen; Anirudra Paul; Khalil A Abboud; Daniel Seidel
Journal:  Nat Chem       Date:  2020-03-30       Impact factor: 24.427
  3 in total

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