Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers

W. Howson, WP Armstrong, K. Cassidy, R. Novelli, MA Tchorzewska, A. Jaxa-Chamiec, RE Dolle, TJ Hallam, BK Leigh, JE Merritt, KE Moores, TJ Rink

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Abstract

Receptor mediated calcium entry (RMCE) is a now recognised mechanism by which the influx of Ca2+ into cells can occur. Agents which antagonise or block this mechanism are expected to possess anti-platelet aggregation and anti-inflammatory activities. The first series of RMCE blockers based upon the lead compound SC 38249, has been prepared. Their synthesis, activity against ADP evoked Ca2+ signals in human platelets and their anti-platelet aggregation activity is described. A trend between the c log P of these compounds and their activity as inhibitors of Ca2+ influx into human platelets stimulated by ADP was observed. This SAR study led to a 40-fold increase in activity over the initial lead compound.

Original languageEnglish
Pages (from-to)595-602
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume25
Issue number7
DOIs
StatePublished - Sep 1990
Externally publishedYes

Keywords

  • Ca influx
  • anti-platelet aggregation
  • c log P
  • receptor mediated calcium entry

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    Howson, W., Armstrong, WP., Cassidy, K., Novelli, R., Tchorzewska, MA., Jaxa-Chamiec, A., Dolle, RE., Hallam, TJ., Leigh, BK., Merritt, JE., Moores, KE., & Rink, TJ. (1990). Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers. European Journal of Medicinal Chemistry, 25(7), 595-602. https://doi.org/10.1016/0223-5234(90)90184-5