Safer drug design

Catalyzed by the progress made in sequencing the human genome, the new field of pharmacogenomics offers the promise of being able to make available a host of new rationally designed, safer drugs. 

N. Bodor, Novel Approaches to the Design of Safer Drugs Soft Drugs and Site-Specific Chemical Delivery Systems , in Advances in Drug Research , Ed. B. Testa, Academic Press, London, Vol. 13, 1984, p. 255-331. 

N. Bodor (1984). Novel approaches to the design of safer drugs soft drugs and site-specific... 

G. Other considerations Serono conducted the comparative study to demonstrate that Rebif is clinically superior to Avonex. No other path was available for Serono to have the product licensed by the FDA before mid-2003 because Avonex carried an orphan drug designation based on its superior safety profile over Betaseron, the first interferon beta to be licensed for multiple sclerosis. Based on the results of the Rebif versus Avonex study, the FDA determined that Rebif is clinically superior to Avonex. While recognizing that the safety profile associated with Rebif is not as favorable as the safety profile of Avonex, the FDA has determined that the severity and frequency of such adverse events do not render Rebif unUcensable under Section 35 of the Public Health Service Act. Further, under the orphan drug regulations, if Serono demonstrates that Rebif is superior to Avonex based on efficacy, Serono does not have to show that Rebif is safer than, or as safe as, Avonex. 

Aridns, E.J. (1980) Design of safer chemicals, (ed. E.J. Aridns) Drug Design, Medicinal Chemistry, a Series of Monographs, Vol. IX, Academic Press, New York, pp. 1 -6. 

Medicinal chemists have, for many years, used QSARs as a tool for drug design. The EPA has used QSARs since 1981 to predict the aquatic toxicity of new, untested commercial chemical substances in the absence of test data. Chemists who are interested in designing safer chemicals will find QSARs very helpful, as they enable one to assess rapidly the toxicity of substances without having to synthesize and test the substances. 

Isosteric Substitution in the Design of Safer Drug Substances... 

As for the design of safer drug substances, isosteric substitution has been used for many years for the design of safer pesticide substances, although to a lesser extent. Isosteric replacement of carbon with silicon, for example, has resulted in a number of safe but effective pesticides [76]. An example of the use of isosteric substitution of carbon with silicon in the design of safer a pesticide is in the case of the insecticide MTI-800 (40) and its much less toxic silane isostere, 41. 

The application of isosterism for the design of safer commercial chemicals is much less common than it is for the design of safer drugs or pesticides. There are some examples, however, of how isosterism has been used to design safer commercial chemical substances. One very successful application is in the case of metallized azo dyes [82, 83]. Historically, chromium was a metal of choice in many metallized azo dyes because it imparts the desired color and fastness. Hexavalent chromium (Cr6+) was often used in making such dyes. 

Based on the examples provided above and the many successful applications of isosterism in the design of safer drugs and pesticides, it appears that isosteric replacement should have an expanded role in the design of safer commercial chemicals, especially since isosteric substitution has the added marketing advantage that it may enable one to circumvent chemicals protected by patents and marketed by competitors. 

N. Bodor and M.-J. Huang, Computational approaches to the design of safer drugs and their molecular properties, Computational Chemistry Reviews of Current Trends, Vol. 1 (J. Leszczynski, ed.) World Scientific, Singapore, 1996, p. 219. 

N. Bodor, Designing safer drugs based on the soft drug approach, Trends Pharmacol. Sci. 3 53 (1982). 

N. Bodor, The application of soft drug approaches to the design of safer corticosteroids, Topical Corticosteroid Therapy A Novel Approach to Safer Drugs (E. Christophers, A. M. Kligman, E. Schopf, and R. B. Stoughton, eds.) Raven Press Ltd, New York, 1988, p. 13. 

T. A. BaiUie, Drug discovery and development in the post-genome era. Can we rationally design safer drugs Adv. Mass Spectrom. 16 (2004), 1-18. 

P.P. Mager, Multidimensional Pharmacochemistry, Design of Safer Drugs. Academic Press, New York, 1984. 

Benigni R, Zito R. Designing safer drugs (Q)SAR-based identification of mutagens and carcinogens. Curr Top Med Chem 2003 3 1289-300. 

Computational Approaches to the Design of Safer Drugs and Their Molecular Properties (N. Bodor M.-J. Huang)... 

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