2. Academic Validation
  3. 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)

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

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada. claudio_sturino@merck.com
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z