Identification of Promising New Molecules in the Discovery Phase

The characterization and optimization of the safety and efficacy of drug candidates in the discovery phase of drug development are crucial to prevent drug failure and to predict clinical outcomes during advanced phases. This post will discuss the various aspects and strategies of identifying lead compounds in early drug development.

Physiochemical properties of candidate drugs

The broad availability of chemical compound libraries and automatic screening platforms has made it relatively easy for selecting initial new drug targets. The medicinal chemist Christopher Lipinski and his colleagues analyzed more than 2,000 drugs and established the so-called “rule of five” for lead drug candidates that are more likely to be membrane permeable and easily absorbed by the body. They concluded that the compound should have the following properties:

  • a molecular weight less than 500
  • a partition coefficient (logP – a measure of lipophilicity) less than 5
  • no more than 5 hydrogen bond donors
  • no more than 10 hydrogen bond acceptors

Current compound collections contain many molecules that violate the rule of five, especially for maintaining a molecular weight of under 500; however, most successful small molecular drugs have molecular weights below 500 and logP values below 5, and failed compounds tend to fall outside this range.

Determination of the therapeutic index

The therapeutic index – a quantitative relationship between drug efficacy (pharmacology) and safety (toxicology) – is often used as an indicator for selecting drug candidates in early drug development. A high therapeutic index, that is, a high ratio of the highest dose of the drug that results in no toxicity (termed no observable adverse effect level, NOAEL) to the dose that leads to the desired pharmacological effect, is preferable for a drug to be considered as having a favorable safety profile while achieving the desired efficacy.

One strategy for evaluating the therapeutic index is to integrate pharmacology and preliminary safety evaluation at several exposure levels within the same study; that is, adding the safety end points (e.g., safety biomarkers, histopathology of target organs) to early pre-clinical efficacy studies (e.g., multidose pharmacology studies) during candidate selection.

Plasma exposure to the drug is usually an indicator of tissue exposure and tissue toxicity. When considering the plasma exposure parameter for predicting the therapeutic index of a drug, researchers will often explore the free drug concentration at the site of action that exerts the biological activity in animal studies. For in vitro studies, IC50 is most often used to quantitatively describe pharmacological effects. In addition, target selectivity – the off-target IC50 dived by the on-target IC50 of the drug – is also an important parameter when assessing the therapeutic index.

Animal models for prediction of adverse effects

One of the main reasons that lead to drug failure during advanced phases is lack of correlation of animal models to human diseases. To date, the prediction of adverse effects using pre-clinical animal models remains a considerable challenge. In selecting animal models for conducting pre-clinical toxicity studies, it is crucial to consider the following criteria: the similarity of the toxicity mechanism to humans, adequate exposure, and presence of human metabolites.

For assessing pharmacological mechanism-based toxicity, it is ideal to demonstrate the desired pharmacodynamic activity in the selected animal model. However, when this is unachievable, efforts are needed to develop surrogate molecules that produce desired pharmacodynamic activity. Alternatively, genetically modified mouse models can be used. For example, the heterozygous superoxide dismutase 2 (Sod2+/-) knockout mouse model was used to uncover the potential of mitochondrial toxicity by the NSAID nimesulide.

ADME parameters

Last but not least, the assessment of ADME (i.e., absorption, distribution, metabolism, excretion) is important for the decision whether to advance, hold, or terminate a drug candidate (a discussion related to this topic was posted on the Nov. 10 blog).

In summary, diverse challenges lie in the search for lead drug candidates; several strategies – optimal physiochemical properties, the balance between safety and efficacy, animal model selection, and superior ADME parameters – should be employed to increase the success rates of developing viable new drugs.

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Categories: Toxicology and Pharmacology

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