Selection of heterocycles for drug design.

ABSTRACT

A method has been devised to obtain heterocyclic ring systems suitable for use in drug design and library design, with an emphasis on the selection of systems with good absorption, distribution, metabolism, excretion and toxicity (ADMET) properties in man. This has been achieved by extraction of the ring systems found in drugs that have reached Phase II or later stages of drug development and launch. Properties have been calculated for these ring systems to enable them to be rationally selected from the database, including descriptors based on molecular size, shape, hydrogen bonding and orbital properties. In many cases, the properties have been calculated for different attachment points of the same heterocycle. Principal components analysis has been used to enable visualization of the set of heterocycles in a useful "chemical space". Using this space, it is possible to select heterocycles for drug design to explore specific aspects of the properties of the heterocycle, such as size or hydrogen bonding, while maintaining other parameters near constant, or to select heterocycles with extreme values of these properties but which are nonetheless likely to be acceptable in a drug. The differences between the properties calculated for the most- and least-frequently used heterocycles from the late-phase drug set have been analyzed, and may suggest that heterocycles in successful drugs are more likely to have calculated quantities associated with lower chemical reactivity.