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
  • 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: [email protected].
  • 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: [email protected].
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.
Products