Xiaochuan Yang | Johns Hopkins University School of Medicine (original) (raw)

Papers by Xiaochuan Yang

Research paper thumbnail of Design, Synthesis, and StructureActivity Relationship, Molecular Modeling, and NMR Studies of a Series of a Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase4 Inhibitors

Journal of Medicinal Chemistry, 2008

Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the ... more Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and antiinflammatory factor palmitoylethanolamide. In the present study, we report on the design, synthesis, and structure-activity relationships (SAR) of a novel class of potent, selective, and systemically active inhibitors of FAAH activity, which we have recently shown to exert potent anxiolytic-like effects in rats. These compounds are characterized by a carbamic template substituted with alkyl or aryl groups at their O-and N-termini. Most compounds inhibit FAAH, but not several other serine hydrolases, with potencies that depend on the size and shape of the substituents. Initial SAR investigations suggested that the requirements for optimal potency are a lipophilic N-alkyl substituent (such as n-butyl or cyclohexyl) and a bent O-aryl substituent. Furthermore, the carbamic group is essential for activity. A 3D-QSAR analysis on the alkylcarbamic acid aryl esters showed that the size and shape of the O-aryl moiety are correlated with FAAH inhibitory potency. A CoMSIA model was constructed, indicating that whereas the steric occupation of an area corresponding to the meta position of an O-phenyl ring improves potency, a region of low steric tolerance on the enzyme active site exists corresponding to the para position of the same ring. The bent shape of the O-aryl moieties that best fit the enzyme surface closely resembles the folded conformations observed in the complexes of unsaturated fatty acids with different proteins. URB524 (N-cyclohexylcarbamic acid biphenyl-3-yl ester, 9g) is the most potent compound of the series (IC 50 ) 63 nM) and was therefore selected for further optimization.

Research paper thumbnail of Boronic Acid-modified DNA that Changes Fluorescent Properties upon Carbohydrate Binding

A long wavelength boronic acid-modified TTP (NB-TTP) has been synthesized and enzymatically incor... more A long wavelength boronic acid-modified TTP (NB-TTP) has been synthesized and enzymatically incorporated into DNA. Such DNA shows intrinsic fluorescent changes upon carbohydrate addition.

Research paper thumbnail of Design, Synthesis, and StructureActivity Relationship, Molecular Modeling, and NMR Studies of a Series of a Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase4 Inhibitors

Journal of Medicinal Chemistry, 2008

Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the ... more Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and antiinflammatory factor palmitoylethanolamide. In the present study, we report on the design, synthesis, and structure-activity relationships (SAR) of a novel class of potent, selective, and systemically active inhibitors of FAAH activity, which we have recently shown to exert potent anxiolytic-like effects in rats. These compounds are characterized by a carbamic template substituted with alkyl or aryl groups at their O-and N-termini. Most compounds inhibit FAAH, but not several other serine hydrolases, with potencies that depend on the size and shape of the substituents. Initial SAR investigations suggested that the requirements for optimal potency are a lipophilic N-alkyl substituent (such as n-butyl or cyclohexyl) and a bent O-aryl substituent. Furthermore, the carbamic group is essential for activity. A 3D-QSAR analysis on the alkylcarbamic acid aryl esters showed that the size and shape of the O-aryl moiety are correlated with FAAH inhibitory potency. A CoMSIA model was constructed, indicating that whereas the steric occupation of an area corresponding to the meta position of an O-phenyl ring improves potency, a region of low steric tolerance on the enzyme active site exists corresponding to the para position of the same ring. The bent shape of the O-aryl moieties that best fit the enzyme surface closely resembles the folded conformations observed in the complexes of unsaturated fatty acids with different proteins. URB524 (N-cyclohexylcarbamic acid biphenyl-3-yl ester, 9g) is the most potent compound of the series (IC 50 ) 63 nM) and was therefore selected for further optimization.

Research paper thumbnail of Boronic Acid-modified DNA that Changes Fluorescent Properties upon Carbohydrate Binding

A long wavelength boronic acid-modified TTP (NB-TTP) has been synthesized and enzymatically incor... more A long wavelength boronic acid-modified TTP (NB-TTP) has been synthesized and enzymatically incorporated into DNA. Such DNA shows intrinsic fluorescent changes upon carbohydrate addition.