92 =1N ORG.4NIC CHEMIST AT LriICGE [I’mc. SOC. ,4iza2jt. Chem. An Organic Chemist at Large BY I;. L. ROSE* (Imperial Chemical Industvies Limited Phavmareztica!s Divisioiz Jlereside Alderley Park LWacclesjield Cheshire SKI0 4TG) DR. ROSE began by comparing the state of cheiiiotherapeutic practice in the years immediately preceding World War TI with that of the present. I t was difficult to realise that in such comparatively recent times there were no really effective remedies for a host of killing and disabling diseases. There was little for example that could be done apart from easing the symptoms for conditions such as typhoid cholera tuberculosis pneumonia and infections due to the streptococcus and staphylococcus while treatments for many tropical diseases such as leprosy sleeping sickness and malaria were non-existent insufficient or prohibitively expen- sive.Today the situation is entirely changed and a disease for example like pneumonia from which 30 years ago people would have been dying in their tens of thousands in the U.K. alone at this time of year has become almost a rarity. Over the same period of time the expectation of life for a new-born child in this country has increased by nearly 15 years due in no small measure to the effectiveness of modern chemotherapy. A further illustration of progress provided by Dr. Rose was in the number of synthetic agents currently in the R.P. (about 250) compared with the mid-thirties (25). In his own organisation almost four thousand new compounds were examined each year for therapeutic effect. On average about twenty of these (depending where the line was drawn) could be regarded as potential candidates for clinical or field (veterinary) trial and bexan the rigorous course of pharmacological and toxicity tests.Perhaps two three or four survived but further loss was usual in the final phase in man. Occasionally also a product had to be withdrawn after addition to the selling range. When this happened it represented a tremendous loss in time highly sophisticated scientific endeavour and of course money. Indeed the research and development cost of each new drug was nowadays not far short of two million pounds. Under these circumstances it was incumbent upon research management to rationalise the approach to new discovery as much as possible and Dr. Rose illustrated from his own experi- ences over the years the various ways in which this was attempted.From the purely theore- tical point of view the most satisfying and aesthetic leads had been provided by the extension of the so-called Woods-Fildes hypothesis whereby a drug was designed from knowledge of the chemistry i.e. the biochemistry of the disease condition involved be it caused by the invasion of the animal body by parasitic cells such as bacteria or protozoa or by aberration of normal body function. In the event a great deal of work had proceeded along these lines and much had been learned about the interaction of chemical substances with cell systems but unfor- tunately the tally of new and useful drugs had been disappointingly small. Dr. Rose analysed some of the causes behind this seeming failure and placed particular stress on the matter of drug access to the target disease-producing cell in the aniinal body.In practice the design of a structure with the necessary pharmacodynamic properties was usually much more difficult than devising a molecule having the desired action on the isolated cell system as measured in vitro for example. This was true even in the simplest cases where an infection of the blood stream was involved and Dr. Rose illustrated this point by reference to the very different concentrations attained in the blood following the oral administration of sulphanilamide derivatives with slightly varied structures. Notwithstanding this large area of uncertainty the “rational approach” was still intensively pursued and Dr. Rose showed how an I.C.I. investigation on specific growth factors for a disease produced by acid-fast bacilli in cattle had been generalised into a search for potential drugs for the treatment of tuberculosis and leprosy so far without success even after 10 years of study.Another current line of work illustrated the approach based on the marriage of new heterocyclic chemistry with the simula- tion of the structure of a naturally occurring compound in the search for new anti-asthmatic drugs and served to show how easy it still was to encounter a toxic manifestation in man which had no counterpart in the earlier laboratory findings. (ith 1970 and reported in the March issue of PYoceedings (p. 41). *Summary of the paper presented after the Annual General Xeeting of the Society held on March June 19701 REPORTS OF MEETINGS 93 Finally Dr. Rose described some of the very recent and unique researches on drugs for the treatment of cardiac conditions but mainly to highlight yet another example of the dis- covery of toxic side effects in the laboratory this time an obscure inalignant process in mice thought to be due to the metabolic production of an aziridine derivative. This particular example was of especial interest to analytical chemists as it showed how the need for the almost impossible task of detecting this labile substance was by-passed by circumstantial but convincing evidence provided by chemical ingenuity.