Literature DB >> 24900795

Himbacine-derived thrombin receptor antagonists: c7-aminomethyl and c9a-hydroxy analogues of vorapaxar.

Mariappan V Chelliah1, Samuel Chackalamannil1, Yan Xia1, William J Greenlee1, Ho-Sam Ahn1, Stan Kurowski1, George Boykow1, Yunsheng Hsieh1, Madhu Chintala1.   

Abstract

We have synthesized several C7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K i = 5 nM). We have also synthesized a C9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.

Entities:  

Keywords:  Himbacine; PAR-1 antagonist; platelet aggregation; thrombin receptor; vorapaxar

Year:  2013        PMID： 24900795      PMCID： PMC4027727          DOI： 10.1021/ml400452v

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


  20 in total

Review 1.  Protease-activated receptors in vascular biology.

Authors:  S R Coughlin
Journal:  Thromb Haemost       Date:  2001-07       Impact factor: 5.249

2.  Discovery of a vorapaxar analog with increased aqueous solubility.

Authors:  Yan Xia; Samuel Chackalamannil; William J Greenlee; Yuguang Wang; Zhiyong Hu; Yuriko Root; Jesse Wong; Jianshe Kong; Ho-Sam Ahn; George Boykow; Yunsheng Hsieh; Stan Kurowski; Madhu Chintala
Journal:  Bioorg Med Chem Lett       Date:  2010-09-15       Impact factor: 2.823

3.  Binding of a thrombin receptor tethered ligand analogue to human platelet thrombin receptor.

Authors:  H S Ahn; C Foster; G Boykow; L Arik; A Smith-Torhan; D Hesk; M Chatterjee
Journal:  Mol Pharmacol       Date:  1997-02       Impact factor: 4.436

4.  Metabolism-based identification of a potent thrombin receptor antagonist.

Authors:  Martin C Clasby; Samuel Chackalamannil; Michael Czarniecki; Dario Doller; Keith Eagen; William Greenlee; Grace Kao; Yan Lin; Hsingan Tsai; Yan Xia; Ho-Sam Ahn; Jacqueline Agans-Fantuzzi; George Boykow; Madhu Chintala; Carolyn Foster; April Smith-Torhan; Kevin Alton; Matthew Bryant; Yunsheng Hsieh; Janice Lau; Jairam Palamanda
Journal:  J Med Chem       Date:  2007-01-11       Impact factor: 7.446

5.  High-affinity thrombin receptor (PAR-1) ligands: a new generation of indole-based peptide mimetic antagonists with a basic amine at the C-terminus.

Authors:  Han Cheng Zhang; Kimberly B White; David F McComsey; Michael F Addo; Patricia Andrade-Gordon; Claudia K Derian; Donna Oksenberg; Bruce E Maryanoff
Journal:  Bioorg Med Chem Lett       Date:  2003-07-07       Impact factor: 2.823

6.  Vorapaxar in the secondary prevention of atherothrombotic events.

Authors:  David A Morrow; Eugene Braunwald; Marc P Bonaca; Sebastian F Ameriso; Anthony J Dalby; Mary Polly Fish; Keith A A Fox; Leslie J Lipka; Xuan Liu; José Carlos Nicolau; A J Oude Ophuis; Ernesto Paolasso; Benjamin M Scirica; Jindrich Spinar; Pierre Theroux; Stephen D Wiviott; John Strony; Sabina A Murphy
Journal:  N Engl J Med       Date:  2012-03-24       Impact factor: 91.245

Review 7.  Cellular consequences of thrombin-receptor activation.

Authors:  R J Grand; A S Turnell; P W Grabham
Journal:  Biochem J       Date:  1996-01-15       Impact factor: 3.857

8.  Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents.

Authors:  Samuel Chackalamannil; Yan Xia; William J Greenlee; Martin Clasby; Darìo Doller; Hsingan Tsai; Theodros Asberom; Michael Czarniecki; Ho-Sam Ahn; George Boykow; Carolyn Foster; Jacqueline Agans-Fantuzzi; Matthew Bryant; Janice Lau; Madhu Chintala
Journal:  J Med Chem       Date:  2005-09-22       Impact factor: 7.446

9.  Basic and translational research on proteinase-activated receptors: antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease.

Authors:  Madhu Chintala; Kenji Shimizu; Masami Ogawa; Hiroya Yamaguchi; Masaki Doi; Peder Jensen
Journal:  J Pharmacol Sci       Date:  2008-12       Impact factor: 3.337

Review 10.  Antiplatelet therapy: in search of the 'magic bullet'.

Authors:  Shaun P Jackson; Simone M Schoenwaelder
Journal:  Nat Rev Drug Discov       Date:  2003-10       Impact factor: 84.694
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  1 in total

Review 1.  Multitargeting nature of muscarinic orthosteric agonists and antagonists.

Authors:  Jaromir Myslivecek
Journal:  Front Physiol       Date:  2022-09-06       Impact factor: 4.755
  1 in total

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