- TARGETING NANOPARTICLES
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Disclosed herein is a composition comprising a plurality of liposomes having an average diameter of less than 400 nanometers, wherein the plurality of liposomes comprise: a first lipid or phospholipid; a second lipid or phospholipid which is derivatized with a polymer; and a sterically bulky excipient capable of stabilizing the liposomes; a third lipid or phospholipid derivatized with a polymer terminated with an integrin targeting component; DSPE or a fourth lipid or phospholipid derivatized with a group binding a contrast enhancing agent wherein the plurality of liposomes optionally encapsulates a payload component consisting of one or more bioactive agents.
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Paragraph 00159; 00161
(2018/11/22)
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- Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein
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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.
- 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.
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p. 3891 - 3904
(2007/10/03)
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