Yuguang Wang

Design and synthesis of piperidinyl piperidine analogues as potent and selective M2 muscarinic receptor antagonists.

Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration.

Streamflow response to climate and landuse changes in a coastal watershed in North Carolina

It is essential to examine the sensitivity of hydrologic responses to climate and landuse change across different physiographic regions in order to formulate sound water management policies for local response to projected global change. This study used the U.S. Geological Surveys Precipitation Runoff Modeling System (PRMS) model to examine the potential impacts of climate and landuse changes on the monthly streamflow of the Trent River basin on the lower coastal plain of eastern North Carolina. The model was first calibrated and then validated using measured, historic, long-term daily streamflow. The model performed satisfactorily for simulating monthly streamflow, as indicated by an overall Nash-Sutcliffe simulation efficiency greater than 0.85. We examined the sensitivity of streamflow to changes in air temperature and precipitation. The simulations suggested that streamflow of individual years could change from -93% to 238%, depending on the two global circulation model (GCM) scenarios used (i.e., HadCMSul2 and CGC1). Streamflow of the Trent River will decrease with an increase in air temperature, and increase (or decrease) with an increase (or decrease) in precipitation. Streamflow was more sensitive to prescribed changes in precipitation than to air temperature for the study area, given its high and stable evapotranspiration rates in the humid climatic environment. Seven hypothetical landuse change scenarios representing forest conversion to crop lands and urban areas indicated that water yield could increase by 14% to 20%. The likely impacts of landuse changes may not be as high as those caused by predicted changes in climate, but moderate urbanization and extreme hydrologic events caused by climate change could pose significant water quantity and quality problems in the Trent River basin.

Design and synthesis of ether analogues as potent and selective M2 muscarinic receptor antagonists

Novel, selective M2 muscarinic antagonists, which replace the metabolically labile styrenyl moiety of the prototypical M2 antagonist 1 with an ether linkage, were synthesized. A detailed SAR study in this class of compounds has yielded highly active compounds that showed M2 Ki values of < 1.0 nM and >100-fold selectivity against M1, M3, and M5 receptors.

An efficient synthesis of Wiedendiol-A from (+)-sclareolide

An efficient synthesis of Wiedendiol-A (1) is described starting from commercially available (+)-sclareolide. This synthesis also confirms the absolute stereochemistry of Wiedendiol-A.

Highly potent and selective inhibitors of endothelin converting enzyme

Abstract Phosphinic acid derivatives, represented by structure 1 , have been synthesized and evaluated as endothelin converting enzyme (ECE) inhibitors. Several of these compounds (for example, 1b , 1c , and 1f ) were found to be potent inhibitors of ECE with a high degree of selectivity against neutral endopeptidase (NEP).

Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors.

We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).

An enantioselective route to trans-2,6-disubstituted piperidines

Abstract The synthesis of ( S )-2-methyl tetrahydropyridine-N-oxide ( 4 ), a key intermediate for the enantioselective construction of trans -2,6-disubstituted piperidines via [3+2] nitrone cycloaddition reaction, is described. Nitrone 4 was elaborated to the fire ant venom alkaloid (+)-solenopsin-A ( 2 ) via intermediate 14 .

Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

Novel inhibitors of cholesteryl ester transfer protein

Abstract The synthesis and CETP inhibitory activity of a series of compounds related to wiedendiols ( 1a,1b ) are reported. It is proposed that a two point pharmacophore consisting of a catechol group and a large hydrophobic anchor is necessary for activity.

Sulfide analogues as potent and selective M2 muscarinic receptor antagonists

We have discovered highly potent, selective sulfide M(2) receptor antagonists with low molecular weight and different structural features compared with our phase I clinical candidate Sch 211803. Analogue 30 showed superior M(2) receptor selectivity profile over Sch 211803. More importantly, this study provided new leads for the discovery of M(2) receptor antagonists as potential drug candidates.