571170-84-8Relevant articles and documents
Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4- tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524)
Sturino, Claudio F.,O'Neill, Gary,Lachance, Nicolas,Boyd, Michael,Berthelette, Carl,Labelle, Marc,Li, Lianhai,Roy, Bruno,Scheigetz, John,Tsou, Nancy,Aubin, Yves,Bateman, Kevin P.,Chauret, Nathalie,Day, Stephen H.,Lévesque, Jean-Fran?ois,Seto, Carmai,Silva, Jose H.,Trimble, Laird A.,Carriere, Marie-Claude,Denis, Danielle,Greig, Gillian,Kargman, Stacia,Lamontagne, Sonia,Mathieu, Marie-Claude,Sawyer, Nicole,Slipetz, Deborah,Abraham, William M.,Jones, Tom,McAuliffe, Malia,Piechuta, Hana,Nicoll-Griffith, Deborah A.,Wang, Zhaoyin,Zamboni, Robert,Young, Robert N.,Metters, Kathleen M.
, p. 794 - 806 (2007/10/03)
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 μM for 6 and 3900 μM 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.
NIACIN RECEPTOR AGONISTS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
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Page/Page column 101, (2010/11/30)
The present invention relates to niacin receptor agonists of formula: (I); as well as pharmaceutically acceptable salts and solvates. The compounds are useful for treating dyslipidemias, and in particular, reducing serum LDL, VLDL and triglycerides, and raising HDL levels. Pharmaceutical compositions and methods of treatment are also included.