Process chemistry and Development

Lead Optimization

Drug Discovery

Discovery is the identification of novel active chemical compounds, often called "hits", which are typically found by assay of compounds for a desired biological activity. Initial hits can come from repurposing existing agents toward a new pathologic processes, and from observations of biologic effects of new or existing natural products from bacteria, fungi, plants, etc. In addition, hits also routinely originate from structural observations of small molecule "fragments" bound to therapeutic targets (enzymes, receptors, etc.), where the fragments serve as starting points to develop more chemically complex forms by synthesis. Finally, hits also regularly originate from en-masse testing of chemical compounds against biological targets, where the compounds may be from novel synthetic chemical libraries known to have particular properties (kinase inhibitory activity, diversity or drug-likeness, etc.), or from historic chemical compound collections or libraries created through combinatorial chemistry. While a number of approaches toward the identification and development of hits exist, the most successful techniques are based on chemical and biological intuition developed in team environments through years of rigorous practice aimed solely at discovering new therapeutic agents.

Further chemistry and analysis is necessary, first to identify and "triage" compounds that do not provide series displaying suitable SAR and chemical characteristics associated with long-term potential for development, then to improve remaining hit series with regard to the desired primary activity, as well as secondary activities and physiochemical properties such that the agent will be useful when administered in real patients. In this regard, chemical modifications can improve the recognition and binding geometries (pharmacophores) of the candidate compounds, and so their affinities for their targets, as well as improving the physicochemical properties of the molecule that underlie necessary pharmacokinetic/pharmacodynamic (PK/PD), and toxicologic profiles (stability toward metabolic degradation, lack of geno-, hepatic, and cardiac toxicities, etc.) such that the chemical compound or biologic is suitable for introduction into animal and human studies.

The next through final synthetic chemical stages involve production of lead compound in suitable quantity and quality to allow large scale animal and eventual, extensive human clinical trials. This involves the optimization of the synthetic route for bulk industrial production, and discovery of the most suitable drug formulation. The former of these is still the bailiwick of medicinal chemistry, the latter brings in the specialization of formulation science (with its components of physical and polymer chemistry and materials science). The synthetic chemistry specialization in medicinal chemistry aimed at adaptation and optimization of the synthetic route for industrial scale syntheses of 100's of kilograms or more is termed process synthesis, and involves thorough knowledge of acceptable synthetic practice in the context of large scale reactions (reaction thermodynamics, economics, safety, etc.). Critical at this stage is the transition to more stringent GMP requirements for material sourcing, handling, and chemistry.

Дата добавления: 2014-11-18