Current Topics in Medicinal Chemistry - Volume 12, Issue 11, 2012

Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3’,5’- cyclic adenosine monophosphate (cAMP) and/or 3’,5’-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both i Read More

Drug discovery is a highly complex process requiring scientists from wide-ranging disciplines to work together in a well-coordinated and streamlined fashion. While the process can be compartmentalized into well-defined functional domains, the success of the entire enterprise rests on the ability to exchange data conveniently between these domains, and integrate it in meaningful ways to support the design, execution and interpr Read More

Determination of drug distribution in brain and other tissues is important in pharmaceutical research. Tissue drug levels need to be determined routinely as they are usually diagnostic for both efficacy and toxicity. Determination of tissue levels in small organ subregions is frequently performed due to important functional considerations. These measurements have traditionally been very tedious requiring extensive dis Read More

Supercritical fluid (SF) was discovered 200 years ago, but the use of this fluid as a mobile phase in chromatography only became popular fifty years ago. The development of the supercritical fluid chromatography (SFC) was progressing slowly due to technological problems since ten years; the interest for this chromatographic mode has been growing up as the construction of the SFC instruments is more or less similar with HPL Read More

In this paper we report the development of chromatographic methods for the separation of 8 biologically active hydroxycholesterols (OHC’s) which include the single-hydroxyl addition species 7α-OHC, 7β-OHC, 25-OHC and 27- OHC, together with the double-hydroxyl addition species 7α, 25-OHC, 7β, 25-OHC, 7α, 27-OHC, and 7β, 27-OHC. Four complementary techniques were employed (gas chromatography, normal phase and re Read More

A small-molecule drug discovery effort can benefit from having several chemical series. Where multiple series are not available, it is often the goal of a project to find novel scaffolds. Structural studies of ligand/protein complexes provide important information on the interactions driving binding. By generalizing these, it is possible to find molecules lacking in similarity in their connectivity yet retaining the ability to interact with the Read More

A major strategy used in drug design is the inhibition of enzyme activity. The ability to accurately measure the concentration of the inhibitor which is required to inhibit a given biological or biochemical function by half is extremely important in ranking compounds. Since the concept of the half maximal inhibitory concentration (IC50) is used extensively for studying reversible inhibition enzymatic reactions, it is important to clearl Read More

Various CYP time-dependent inhibition (TDI) assays have been widely implemented in drug discovery and development which has led to great success in positively identifying compounds with mechanism-base inhibition liability. However, drug-drug interaction (DDI) predictions by various in-silico models utilizing kinetic parameters obtained from TDI assays have met with significant challenges including questionable kinetic da Read More

Increasing pressure on the pharmaceutical industry to reduce cost and focus internal resources on “high value” activities is driving a trend to outsource traditionally “in-house” drug discovery activities. Compound collections are typically viewed as drug discovery’s “crown jewels”; however, in late 2007, Johnson & Johnson Pharmaceutical Research & Development (J&J PRD) took a bold step to move their entire North America Read More