Avoidance of the Ames test liability for aryl-amines via computation.

Aryl-amines are commonly used synthons in modern drug discovery, however a minority of these chemical templates have the potential to cause toxicity through mutagenicity. The toxicity mostly arises through a series of metabolic steps leading to a reactive electrophilic nitrenium cation intermediate that reacts with DNA nucleotides causing mutation. Highly detailed in silico calculations of the energetics of chemical reactions involved in the metabolic formation of nitrenium cations have been performed. This allowed a critical assessment of the accuracy and reliability of using a theoretical formation energy of the DNA-reactive nitrenium intermediate to correlate with the Ames test response. This study contains the largest data set reported to date, and presents the in silico calculations versus the in vitro Ames response data in the form of beanplots commonly used in statistical analysis. A comparison of this quantum mechanical approach to QSAR and knowledge-based methods is also reported, as well as the calculated formation energies of nitrenium ions for thousands of commercially available aryl-amines generated as a watch-list for medicinal chemists in their synthetic optimization strategies.

Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

The impact of fatty acid oxidation on energy utilization: targets and therapy.

Utilization of fat as a long-term energy storage vehicle is crucial for the maintenance of cellular metabolism and is under intricate and many times redundant control mechanisms. Aberrations in the control of energy metabolism is apparent in diseases such as diabetes and obesity and is evident early on in patients with impaired glucose tolerance. Insulin resistance has been observed at the level of muscle, liver and adipose tissue. Hyperglycemia is the hallmark of diabetes and is characterized by decreased glucose disposal and increased glucose production, driven by enhanced and uncontrolled fatty acid oxidation (FAO). Mechanisms aimed at limiting the availability of substrates or the activity of processes involved in FAO should provide an immediate reduction in undesired glucose production in these individuals. Numerous targets are available which influence directly the metabolism of fat, including limiting availability of substrate to FAO, inhibiting oxidation of the fatty acid per se, and uncoupling the energy obtained during the oxidation of the fatty acid. These include antilipolytic agents which limit the availability of substrate, FAO inhibitors which limit fatty acid transport (carnitine palmitoyl transferase, CoA sequestration), FAO per se (beta oxidation), and agents which uncouple the energy of FAO (uncoupling proteins, beta3 agonists). These other targets which affect fatty acid metabolism indirectly will be discussed in this review with 184 references.