Drug candidates optimization

TABLE 16.1 Major Applications of Vascular Perfused Organs in Drug-Candidate Optimization and Development... 

As mentioned previously, the choice of the system or method employed ultimately depends on the question asked and how the data generated are suhsequently used. Advocates of perfused-liver models would argue to determine hrst-pass hepatic clearance in preclinical development, then measure clearance directly, and avoid as many assumptions as possible. Table 16.1 summarizes the major applications of the perfused liver model in drug candidate optimization and subsequent development. As is the case with the gut, the contribution of the liver to the fate and effects of drugs can be influenced by numerous factors, many of which can be studied with the perfused-liver model. These effects include the blood flow, species and gender differences, and induction. 

The drug discovery process can be divided into four subsets acquisition of chemical drug candidates, pharmacodynamic testing of large numbers of compounds (screening), and the optimization of pharmacokinetic and pharmaceutical properties. 

In addition to the in vitro assays described above, physical properties should be calculated for all new compounds designed for synthesis. It is necessary to keep in mind the target values for leads, such as MW < 450, clogP < 4.0, and PSA < 80. It has been demonstrated that properties such as MW and clogP increase during optimization [26], so that a lead needs to have lower values for these properties than a drug candidate. Additional factors that make up the rule-of-five [27] as well as the number of rotatable bonds as described by Veber [28] can also be tracked. While... 

Deprotection of the pMB group from 20 proceeded smoothly in TFA to provide the drug candidate 2. The isolation conditions of a suitable crystal form of 2 for development were optimized later since we had to change the protective group of the nitrogen of 4 for the subsequent asymmetric addition reaction. 

High-throughput screening (HTS) is today the most commonplace method for identifying lead compounds that can be subsequently optimized to generate drug candidates. 

This type of information about a homologous series of drug candidates, when considered in light of the propensity of these compounds to undergo first-pass metabolism and/or liver clearance, allows pharmaceutical scientists to make more intelligent decisions about which compounds to move into animal studies. In addition, when an in vitro-in vivo correlation can be demonstrated for a series of compounds, the results of Caco-2 experiments can be used as a guide by medicinal chemists to make structural modifications to optimize oral bioavailability. 

An approach that integrated structure-based drug design with physicochemical properties-based approaches to optimizing drug candidate... 

Andersen, K. E., Sprensen, J. L Huusfeldt, P. 0., Knutsen, L. J., Lau, J., Lundt, B. F., et al. (1999) Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates../. Med. Chem. 42,4281 4291. 

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