Benign by Design: Summary and Further Reading

To summarise, some steps that can be taken to minimise PBT issues with candidate drugs are listed below:

• Avoid polyhalogenated fragments (F, Cl, Br);
• Avoid fluorine if at all possible;
• Avoid large numbers of fused aromatic rings;
• If possible, the use of aliphatic rings is preferable to benzene/heteroaromatic rings;
• Highly substituted aromatic rings can be problematic;
• Avoid highly branched aliphatics;
• Avoid highly hindered/quaternary carbons if possible;
• Spiro compounds – be alert;
• Esters are preferable to amides;
• For amides, primary > secondary > tertiary;
• Ureas are preferable to sulphonamides;
• High aqueous solubility;
• Log P as low as possible (although most APIs should fall between -0.4 and 5.6[1])
  
• Aim for as low a molecular weight as possible;
• It is beneficial if the compound has a UV/Vis maxima > 290 nm;
• Use ecotoxicity testing earlier on in the development pipeline to highlight potential environmental issues;
• Use predictive tools, but understand their limitations – probably quite good for P and B, not reliable for T (for quantitative measures of ecotoxicity);
• Look for structural similarity with compounds known to have PBT issues;
• Look for plausible degradation pathways that lead to known PBT fragments;
• Make use of ‘read across’ data but understand the associated risks and limitations.