Design, synthesis, and biological evaluation of (2R,alphaS)-3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol as potent and orally active cholesteryl ester transfer protein inhibitor.
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Kuo
Gee-Hong
GH
Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, LLC 8 Clarke Drive, Cranbury, New Jersey 08512, USA. gkuo@its.jnj.com
Rano
Thomas
T
Pelton
Patricia
P
Demarest
Keith T
KT
Gibbs
Alan C
AC
Murray
William V
WV
Damiano
Bruce P
BP
Connelly
Margery A
MA
D000284:Administration, Oral; D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D004041:Dietary Fats / Q000008:administration & dosage; D015195:Drug Design; D006801:Humans; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
C539971:3,4-dihydro-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)-alpha-(trifluoromethyl)-1(2H)-quinolineethanol; D053480:Cholesterol Ester Transfer Proteins; D004041:Dietary Fats; D011804:Quinolines