for Physical Chemists by Physical Chemists

Chemical Reactivity and Stability in Drug Discovery

Dr Linette Ruston, Computational & Physical Chemistry, AstraZeneca, Alderley Park

This talk will cover forced degradation studies that are routinely carried out in drug discovery at AstraZeneca, Alderley Park, to assess chemical reactivity and stability risks and inform molecular design.

The studies involve a range of simple, flexible in-vitro tests that can provide information to answer variety of questions. Kinetic rate profiles and product identification facilitate mechanistic interpretation that assists chemistry design to reduce/avoid stability or reactivity issues. Results aid understanding of compound behaviour under physiological conditions; assist interpretation of biological test results; guide compound handling/storage and inform formulation development. Decomposition kinetics are monitored in solution under a broad range of conditions, predominantly under forced conditions to provide a rapid assessment of compound properties that can then be fed back into compound design within the project. Typical studies include hydrolysis (elevated temperature at various pHs), photolysis and chemical reactivity towards biological nucleophiles such as thiols. 1,2 A simple system to assess susceptibility to oxidation has recently been developed. Examples demonstrating the impact of stability/reactivity data in discovery projects will be presented.

1. P. A. MacFaul, A. D. Morely, J. J. Crawford, Biorg. Med. Chem. Lett. 19 (2009) 1136
2. A. D. Morely, P. W. Kenny, B. Burton, R. A. Heald, P. A. MacFaul, J. Mullett, K. Page, S. S. Porres, L. Rosenbrier Ribeiro, P. Smith, S. Ward, T. J. Wilkinson, Biorg. Med. Chem. Lett. 19 (2009) 1658

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Last modified: 28 April 2008