263347-01-9Relevant academic research and scientific papers
Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein
Durley, Richard C.,Grapperhaus, Margaret L.,Hickory, Brian S.,Massa, Mark A.,Wang, Jane L.,Spangler, Dale P.,Mischke, Deborah A.,Parnas, Barry L.,Fobian, Yvette M.,Rath, Nigam P.,Honda, Dorothy D.,Zeng, Ming,Connolly, Daniel T.,Heuvelman, Deborah M.,Witherbee, Bryan J.,Melton, Michele A.,Glenn, Kevin C.,Krul, Elaine S.,Smith, Mark E.,Sikorski, James A.
, p. 3891 - 3904 (2007/10/03)
A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [3H] cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF2CF2H (42, IC50 0.14 μM in buffer, 5.6 μM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF3 (67), and C(CF3)2OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC50 0.02 μM in buffer, 0.6 μM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.
Substituted N, N-disubstituted diamino compounds useful for inhibiting cholesteryl ester transfer protein activity
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, (2008/06/13)
The invention relates to substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamine compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Preferred tertiary-heteroalkylamine compounds are substituted N,N-disubstituted diamines. A preferred specific N,N-disubstituted diamine is the compound:
