Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524)

  • J Med Chem. 2007 Feb 22;50(4):794-806. doi: 10.1021/jm0603668.
Claudio F Sturino  1 ,  Gary O'Neill ,  Nicolas Lachance ,  Michael Boyd ,  Carl Berthelette ,  Marc Labelle ,  Lianhai Li ,  Bruno Roy ,  John Scheigetz ,  Nancy Tsou ,  Yves Aubin ,  Kevin P Bateman ,  Nathalie Chauret ,  Stephen H Day ,  Jean-François Lévesque ,  Carmai Seto ,  Jose H Silva ,  Laird A Trimble ,  Marie-Claude Carriere ,  Danielle Denis ,  Gillian Greig ,  Stacia Kargman ,  Sonia Lamontagne ,  Marie-Claude Mathieu ,  Nicole Sawyer ,  Deborah Slipetz ,  William M Abraham ,  Tom Jones ,  Malia McAuliffe ,  Hana Piechuta ,  Deborah A Nicoll-Griffith ,  Zhaoyin Wang ,  Robert Zamboni ,  Robert N Young ,  Kathleen M Metters
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada. [email protected]
PMID: 17300164 DOI: 10.1021/jm0603668
Abstract

The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP Antagonist 13.

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