Drug research molecular modification

For those of us who have devoted our lives to medicinal chemistry, and particularly to the search for chemotherapeutic agents in the laboratories of the pharmaceutical industry, events of the past three years have brought bewilderment and chagrin. For the first time our objectives were questioned and our contributions were belittled. These criticisms of us as research workers in medicinal chemistry have left their mark on us—for how else can we explain a Symposium on the Influence of Molecular Modification on Drug Design ... 

Many of the new antimicrobials are clearly outstanding contributions to the art of chemotherapy and are, as such, real triumphs of pharmacological research. Others are molecular modifications of established compounds and are introduced with claims that some desired feature—such as greater potency, more rapid absorption, more sustained blood levels, reduced bacterial resistance, or fewer side effects—has been added to the more familiar properties. Since all such claims need to be viewed skeptically until they have been confirmed by impartial investigators and extended experience, compounds of this type often make only a numerical rather than a qualitative contribution to the list of available drugs, and thus add only confusion. 

Finally and probably most important can be the contribution made by such drugs in further pharmacological research. Contrasting compounds such as morphine and WIN 20,228, which are so similar except for their addiction liability, may provide another tool as valuable as nalorphine for further exploration of the problems of analgesia, physical dependence, tolerance, and the relationship between molecular modification and drug action. 

John J. Jennings Of course it is. I certainly didn t mean to downgrade it at all. I think one of the questions that has been running through the discussions here is research vs. development. Dr. Hoffman pointed out that it took molecular modification or manipulation to make procaine a useful antiarrhythmic drug. Of course, I think this falls somewhere between discovery and development. It is not truly discovery, and yet it is a little bit more than cost-lowering development. 

Friedman, H.L. (1951) Influence of isosteric replacements upon biological activity. National Academy of Sciences-National Research Council Publication No. 206, Washington, DC, pp. 295-395. Thornber, C.W. (1979) Isosterism and molecular modification in drug design. Chemical Society Reviews, 8, 563-580. Hall, S.R., Allen, F.H., and Brown, I.D. (1991) The crystallographic information file (CIF) a new standard archive file for crystallography. Acta Crystallographica A, 47, 655-685. 

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