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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.

Recommended reading:

K. Kümmerer, Benign by Design, in Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry, The Royal Society of Chemistry, 2016, ch. 7, pp. 73-81.

C. Leder, T. Rastogi and K. Kümmerer, Putting benign by design into practice-novel concepts for green and sustainable pharmacy: Designing green drug derivatives by non-targeted synthesis and screening for biodegradability, Sustainable Chemistry and Pharmacy, 2015, 2, 31-36.

C. Rucker and K. Kümmerer, Modeling and predicting aquatic aerobic biodegradation – a review from a user’s perspective, Green Chemistry, 2012, 14, 875-887.

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  1. A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski, A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases, Journal of Combinatorial Chemistry, 1999, 1, 55-68.