Antitarget

In pharmacology, an antitarget is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to ensure that new drugs do not show significant activity at any of a range of antitargets, most of which are discovered largely by chance.[1][2]

Among the best-known and most significant antitargets are the hERG channel and the 5-HT2B receptor, both of which causing long-term problems with heart function that can prove fatal (long QT syndrome and cardiac fibrosis, respectively), in a small but unpredictable proportion of users. Both of these targets were discovered as a result of high levels of distinctive side-effects during the marketing of certain medicines, and, while some older drugs with significant hERG activity are still used with caution, most drugs that have been found to be strong 5-HT2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these targets.[3][4][5][6][7][8]

References

  1. ↑ Klabunde, T.; Evers, A. (2005). "GPCR antitarget modeling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects". Chembiochem : a European journal of chemical biology 6 (5): 876–889. doi:10.1002/cbic.200400369. PMID 15791686.
  2. ↑ Price, D.; Blagg, J.; Jones, L.; Greene, N.; Wager, T. (2009). "Physicochemical drug properties associated with in vivo toxicological outcomes: a review". Expert opinion on drug metabolism & toxicology 5 (8): 921–931. doi:10.1517/17425250903042318. PMID 19519283.
  3. ↑ De Ponti, F.; Poluzzi, E.; Cavalli, A.; Recanatini, M.; Montanaro, N. (2002). "Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview". Drug safety : an international journal of medical toxicology and drug experience 25 (4): 263–286. doi:10.2165/00002018-200225040-00004. PMID 11994029.
  4. ↑ Recanatini, M.; Poluzzi, E.; Masetti, M.; Cavalli, A.; De Ponti, F. (2005). "QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development". Medicinal Research Reviews 25 (2): 133–166. doi:10.1002/med.20019. PMID 15389727.
  5. ↑ Raschi, E.; Vasina, V.; Poluzzi, E.; De Ponti, F. (2008). "The hERG K+ channel: target and antitarget strategies in drug development". Pharmacological research : the official journal of the Italian Pharmacological Society 57 (3): 181–195. doi:10.1016/j.phrs.2008.01.009. PMID 18329284.
  6. ↑ Raschi, E.; Ceccarini, L.; De Ponti, F.; Recanatini, M. (2009). "hERG-related drug toxicity and models for predicting hERG liability and QT prolongation". Expert opinion on drug metabolism & toxicology 5 (9): 1005–1021. doi:10.1517/17425250903055070. PMID 19572824.
  7. ↑ Huang, X.; Setola, V.; Yadav, P.; Allen, J.; Rogan, S.; Hanson, B.; Revankar, C.; Robers, M.; Doucette, C.; Roth, B. L. (2009). "Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment". Molecular Pharmacology 76 (4): 710–722. doi:10.1124/mol.109.058057. PMC 2769050. PMID 19570945.
  8. ↑ Bhattacharyya, S.; Schapira, A. H.; Mikhailidis, D. P.; Davar, J. (2009). "Drug-induced fibrotic valvular heart disease". The Lancet 374 (9689): 577–85. doi:10.1016/S0140-6736(09)60252-X. PMID 19683643.
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