Chiral N,N-Disubstituted Trifluoro-3-Amino-2-Propanols Are Potent Inhibitors of Cholesteryl Ester Transfer Protein

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]ch...

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Published in:Journal of medicinal chemistry 2002-08, Vol.45 (18), p.3891-3904
Main Authors: 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
Format: Article
Language:English
Subjects:
Aniline Compounds - chemical synthesis
Aniline Compounds - pharmacokinetics
Aniline Compounds - pharmacology
Animals
Biological and medical sciences
Carrier Proteins - chemical synthesis
Carrier Proteins - chemistry
Carrier Proteins - pharmacology
Cholesterol Ester Transfer Proteins
Combinatorial Chemistry Techniques
Cricetinae
Crystallography, X-Ray
General and cellular metabolism. Vitamins
Glycoproteins
Humans
Lipoproteins, HDL - blood
Lipoproteins, LDL - blood
Lipoproteins, VLDL - blood
Male
Medical sciences
Mesocricetus
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Phenyl Ethers - chemical synthesis
Phenyl Ethers - pharmacokinetics
Phenyl Ethers - pharmacology
Propanolamines - chemical synthesis
Propanolamines - chemistry
Propanolamines - pharmacology
Protein Binding
Serum Albumin - metabolism
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020038h