The roles of the Pharmacology Core include characterization of the biologically active compounds synthesized by the Chemistry Core, and at later stages, to perform toxicological characterization. Preclinical pharmacokinetic properties encompassing Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) are critical criteria that help determine the potential utility of a drug candidate. A comprehensive knowledge of the ADME/T properties of a compound is important for developing appropriate dosing regimens that result in optimal efficacy. For the initial profiling of biologically active compounds, a battery of in vitro assays are performed, including, cytotoxicity, metabolism in human and mouse liver microsomes, membrane permeability using Caco-2 assays and cytochrome P450 enzyme inhibition. In addition, the Pharmacology Core is also responsible for evaluating the in vivo toxicity profile in rodents. The data generated by these assays will be reported back to the Biology, Chemistry and Efficacy Assessment Cores. Analog synthesis, biological screening, and pharmacological testing will be performed iteratively, allowing for refinement of the lead molecules.
| Nelson, Michael D; Rader, Florian; Tang, Xiu et al. (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085-91 |
