Discovery of novel diarylpyrimidines as potent HIV-1 NNRTIs by investigating the chemical space of a less explored "hydrophobic channel"
A new series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), guided by the comprehensive analysis
Substituted diarylpyrimidine derivative as well as preparation method and application thereof
The invention discloses a substituted diarylpyrimidine derivative as well as a preparation method and application thereof. The substituted diarylpyrimidine derivative or a pharmaceutically acceptable salt or predrug of the substituted diarylpyrimidine der
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Paragraph 0107; 0108
(2017/08/26)
Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies
To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X2 or a 3,5-X2-4-OH phenyl substructure (X = Br or CH3). Coconsideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls or linkage through nonpolar E-olefin or -CH2CH2- substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR·inhibitor crystal structures (1.4-1.8 A?) provide insight into why such linkers afford inhibitors with greater potency and selectivity.
Johnson, Steven M.,Connelly, Stephen,Wilson, Ian A.,Kelly, Jeffery W.
supporting information; experimental part
p. 6348 - 6358
(2009/12/03)
Effect of structure on potency and selectivity in 2,6-disubstituted 4-(2-arylethenyl)phenol lipoxygenase inhibitors
A series of 2,6-disubstituted 4-(2-arylethenyl)phenols with potent human neutrophil 5-lipoxygenase (5-LO) inhibiting activity (IC50s in the 10-7 M range) and weaker human platelet cyclooxygenase (CO) inhibiting activity (IC50/s
Lazer,Wong,Wegner,Graham,Farina
p. 1892 - 1898
(2007/10/02)
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