Seite - (000297) - in Biomedical Chemistry: Current Trends and Developments

physicochemical and pharmacokinetic properties, and computational modeling guide the stepwise structural modifications and should be run in parallel with the different steps. The strategy will be described in the following section, and further exemplified in a case study related to a metabolite to the neuropeptide Substance P (Fransson, 2008; 2010; 2013). Figure 3.3.2: A step-wise strategy for development of drug-like peptidomimetics. 3.3.1.1.1 Property Elucidation The activity at the target and the exposure (e.g. concentration and duration) determine the efficacy of a drug. In the body, several barriers to drug exposure can be found, for example cell membranes, metabolic enzymes, efflux transporters, and binding proteins. How a compound performs at a specific barrier is connected to its drug properties. In the GI tract, compounds can cross the cellular membrane barrier by three major mechanisms (van de Waterbeemd, 2001). The two most common are transcellular absorption, i.e. passive transfer by diffusion across the lipid membranes, and paracellular absorption, which proceeds through aqueous pores at the tight junctions between the cells. The third mechanism is active uptake by transport proteins that usually transport nutrients across the membrane (Kerns, 2008; van de Waterbeemd, 2001). The most important mechanism for drug absorption is passive diffusion, and about 95% of all commercial drugs are absorbed by this route (Kerns, 2008). Metabolizing enzymes in the GI tract, e.g. the cytochrome P450 (CYP) enzymes and proteolytic enzymes as well as efflux