Literature DB >> 27482618

Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin.

Kayla J Temple, Matthew T Duvernay, Summer E Young, Wandong Wen1, Wenjun Wu1, Jae G Maeng, Anna L Blobaum, Shaun R Stauffer2, Heidi E Hamm, Craig W Lindsley2.   

Abstract

Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC50 = 445 nM, PAR1 response IC50 > 30 μM) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 > 30 μM) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin.

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Year:  2016        PMID： 27482618      PMCID： PMC5775816          DOI： 10.1021/acs.jmedchem.6b00928

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  18 in total

1.  Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin.

Authors:  M L Kahn; M Nakanishi-Matsui; M J Shapiro; H Ishihara; S R Coughlin
Journal:  J Clin Invest       Date:  1999-03       Impact factor: 14.808

2.  Thrombin-receptor antagonist vorapaxar in acute coronary syndromes.

Authors:  Pierluigi Tricoci; Zhen Huang; Claes Held; David J Moliterno; Paul W Armstrong; Frans Van de Werf; Harvey D White; Philip E Aylward; Lars Wallentin; Edmond Chen; Yuliya Lokhnygina; Jinglan Pei; Sergio Leonardi; Tyrus L Rorick; Ann M Kilian; Lisa H K Jennings; Giuseppe Ambrosio; Christoph Bode; Angel Cequier; Jan H Cornel; Rafael Diaz; Aycan Erkan; Kurt Huber; Michael P Hudson; Lixin Jiang; J Wouter Jukema; Basil S Lewis; A Michael Lincoff; Gilles Montalescot; José Carlos Nicolau; Hisao Ogawa; Matthias Pfisterer; Juan Carlos Prieto; Witold Ruzyllo; Peter R Sinnaeve; Robert F Storey; Marco Valgimigli; David J Whellan; Petr Widimsky; John Strony; Robert A Harrington; Kenneth W Mahaffey
Journal:  N Engl J Med       Date:  2011-11-13       Impact factor: 91.245

3.  Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.

Authors:  T K Vu; D T Hung; V I Wheaton; S R Coughlin
Journal:  Cell       Date:  1991-03-22       Impact factor: 41.582

4.  Domains specifying thrombin-receptor interaction.

Authors:  T K Vu; V I Wheaton; D T Hung; I Charo; S R Coughlin
Journal:  Nature       Date:  1991-10-17       Impact factor: 49.962

5.  Protease-activated receptor 4 is more important than protease-activated receptor 1 for the thrombin-induced procoagulant effect on platelets.

Authors:  T L Lindahl; A S Macwan; S Ramström
Journal:  J Thromb Haemost       Date:  2016-07-11       Impact factor: 5.824

6.  Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial.

Authors:  Benjamin M Scirica; Marc P Bonaca; Eugene Braunwald; Gaetano M De Ferrari; Daniel Isaza; Basil S Lewis; Felix Mehrhof; Piera A Merlini; Sabina A Murphy; Marc S Sabatine; Michal Tendera; Frans Van de Werf; Robert Wilcox; David A Morrow
Journal:  Lancet       Date:  2012-08-26       Impact factor: 79.321

7.  Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK)

Authors:  J Collinson; M D Flather; K A Fox; I Findlay; E Rodrigues; P Dooley; P Ludman; J Adgey; T J Bowker; R Mattu
Journal:  Eur Heart J       Date:  2000-09       Impact factor: 29.983

8.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.

Authors:  Marc S Sabatine; Christopher P Cannon; C Michael Gibson; Jose L López-Sendón; Gilles Montalescot; Pierre Theroux; Marc J Claeys; Frank Cools; Karen A Hill; Allan M Skene; Carolyn H McCabe; Eugene Braunwald
Journal:  N Engl J Med       Date:  2005-03-09       Impact factor: 91.245

9.  Cloning and characterization of human protease-activated receptor 4.

Authors:  W F Xu; H Andersen; T E Whitmore; S R Presnell; D P Yee; A Ching; T Gilbert; E W Davie; D C Foster
Journal:  Proc Natl Acad Sci U S A       Date:  1998-06-09       Impact factor: 11.205

10.  Synthesis of indole derived protease-activated receptor 4 antagonists and characterization in human platelets.

Authors:  Summer E Young; Matthew T Duvernay; Michael L Schulte; Craig W Lindsley; Heidi E Hamm
Journal:  PLoS One       Date:  2013-06-11       Impact factor: 3.240
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  2 in total

1.  Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles.

Authors:  Kayla J Temple; Matthew T Duvernay; Jae G Maeng; Anna L Blobaum; Shaun R Stauffer; Heidi E Hamm; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-10-11       Impact factor: 2.823

2.  Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

Authors:  Jeanette L Bertron; Matthew T Duvernay; Sidnee G Mitchell; Shannon T Smith; Jae G Maeng; Anna L Blobaum; Dexter C Davis; Jens Meiler; Heidi E Hamm; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2021-12-02       Impact factor: 4.418
  2 in total

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