Literature DB >> 24900880

Himbacine-derived thrombin receptor antagonists: c7-spirocyclic analogues of vorapaxar.

Mariappan V Chelliah1, Keith Eagen1, Zhuyan Guo1, Samuel Chackalamannil1, Yan Xia1, Hsingan Tsai1, William J Greenlee1, Ho-Sam Ahn1, Stan Kurowski1, George Boykow1, Yunsheng Hsieh1, Madhu Chintala1.   

Abstract

We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure-activity relationships in this series.

Entities:  

Keywords:  PAR-1 antagonist; himbacine; thrombin receptor; vorapaxar

Year:  2014        PMID： 24900880      PMCID： PMC4027741          DOI： 10.1021/ml500008w

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


  21 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.  Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist.

Authors:  Anima Ghosal; Xiaowen Lu; Natalia Penner; Lan Gao; Ragu Ramanathan; Swapan K Chowdhury; Narendra S Kishnani; Kevin B Alton
Journal:  Drug Metab Dispos       Date:  2010-10-06       Impact factor: 3.922

3.  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

4.  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

5.  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

6.  Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity.

Authors:  Samuel Chackalamannil; Yuguang Wang; William J Greenlee; Zhiyong Hu; Yan Xia; Ho-Sam Ahn; George Boykow; Yunsheng Hsieh; Jairam Palamanda; Jacqueline Agans-Fantuzzi; Stan Kurowski; Michael Graziano; Madhu Chintala
Journal:  J Med Chem       Date:  2008-05-01       Impact factor: 7.446

7.  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 8.  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

9.  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

10.  High-resolution crystal structure of human protease-activated receptor 1.

Authors:  Cheng Zhang; Yoga Srinivasan; Daniel H Arlow; Juan Jose Fung; Daniel Palmer; Yaowu Zheng; Hillary F Green; Anjali Pandey; Ron O Dror; David E Shaw; William I Weis; Shaun R Coughlin; Brian K Kobilka
Journal:  Nature       Date:  2012-12-09       Impact factor: 49.962
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