Antitarget

In pharmacology, an antitarget is a receptor, enzyme, or other biological target that is affected by a drug, which 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 have been discovered largely through chance.^[1][2]

Among the best known and most significant antitargets are the hERG channel and the 5-HT_2B receptor, both of which cause long-term problems with heart function which can prove fatal (long QT syndrome and cardiac fibrosis respectively), in a small but unpredictable proportion of users. These targets were both 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hERG activity are still used with caution, most drugs that have been found to be strong 5-HT_2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these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.  edit
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.  edit
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. PMID 11994029.  edit
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.  edit
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.  edit
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.  edit
7. ^ Huang, X.; Setola, V.; Yadav, P.; Allen, J.; Rogan, S.; Hanson, B.; Revankar, C.; Robers, M. et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2769050.  edit
8. ^ Bhattacharyya, S.; Schapira, A. H.; Mikhailidis, D. P.; Davar, J. (2009). "Drug-induced fibrotic valvular heart disease". The Lancet 374 (9689): 577. doi:10.1016/S0140-6736(09)60252-X.  edit