2. Academic Validation
  3. Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354

Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354

  • Bioorg Med Chem Lett. 2014 Oct 1;24(19):4708-4713. doi: 10.1016/j.bmcl.2014.08.021.
Wandong Wen 1,  Summer E Young 2,  Matthew T Duvernay 2,  Michael L Schulte 3,  Kellie D Nance 3,  Bruce J Melancon 4,  Julie Engers 4,  Charles W Locuson 2nd 4,  Michael R Wood 5,  J Scott Daniels 4,  Wenjun Wu 6,  Craig W Lindsley 5,  Heidi E Hamm 2,  Shaun R Stauffer 7
Affiliations

Affiliations

  • 1 College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 3 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 4 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
  • 5 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
  • 6 College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China. Electronic address: wuwenjun@nwsuaf.edu.cn.
  • 7 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA. Electronic address: shaun.stauffer@vanderbilt.edu.
PMID: 25176330 DOI: 10.1016/j.bmcl.2014.08.021
Abstract

Herein we report the discovery and SAR of an indole-based Protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM).

Keywords

ML354; PAR-4 antagonist; Protease activated receptor 4.

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