Lewis H. Sarett

On the efficacy of asparagine, glutamine, γ-aminobutyric acid and 2-pyrrolidinone in preventing chemically induced seizures in mice

Abstract Large doses of γ-aminobutyric acid and its lactam 2-pyrrolidinone protect mice against convulsions induced by β-methyl-β-ethylglutarimide (MEG, Megimide R ) but not by electroshock. Asparagine and glutamine are less effective. γ-Aminobutyric acid and 2-pyrrolidinone are of low toxicity in animals and man. Their clinical efficacy as anti-epileptic agents is being investigated.

The Effects of Structural Alteration on the Anti-Inflammatory Properties of Hydrocortisone

The present article attempts to summarize the changes in anti-inflammatory potency which attend structural alteration in the hydrocortisone molecule. An effort has been made to include — insofar as they are known — the principal biological and physical chemical parameters which may account for these changes.

SOME ASPECTS OF THE EVOLUTION OF ANTI-INFLAMMATORY STEROIDS

The synthesis of the anti-inflammatory steroid dexamethasone, 1h-methyl9a-fluoroprednisolone (Decadron*) was carried out in the Research Laboratories Division of Merck & Co., Inc., Rahway, N. J., by G. E. Arth and his associates? The synthetic route was a modified adaptation of previously described procedures for introduction of the required functionality in the A-ring, the C-ring, and the side chain, augmented, however, by the addition of an a-methyl group at C-16.2 The presence of this methyl group gives rise to increased steric hindrance at C-20; hindrance that, on the one hand, impedes chemical introduction of the C-17 hydroxyl group, but eventually confers on the side chain an increased degree of biological ~tabi l i ty .~ The details of our synthetic work will not be related here since, in any case, Eugene Oliveto, elsewhere in this monograph, will describe corresponding studies carried out by his associates. Instead, it may be pertinent on this occasion to review a different aspect of anti-inflammatory steroids, one that has commanded the vigilant interest of many, if not all, United States pharmaceutical research organizations. This aspect is the design of anti-inflammatory steroids. Behind each steroid that has been carried through to synthetic completion there has been an idea, sometimes an incorrect one, without which the attendant synthetic effort would not have been undertaken. It is the development of some of these ideas during the past decade to which I now address myself. t During the first years following the discovery of cortisone by Hench, Slocumb, Polley, and Kendall in 1948, investigation of the synthesis of structural modifications began slowly. There were several good reasons for this. First, cortisone was a natural product, and one of the dominant trends of thought of the period immediately preceding its advent had been the conviction of the superiority of natural products. The vitamins had been discovered and synthesized; each had filled perfectly its role of replacement in deficiency diseases without the necessity of man-made synthetic modifications. The prevailing attitude was: what was made by Nature is necessary and sufficient. Second, the steroid chemists qualied to synthesize new modifications of cortisone were occupied for the most part with a more urgent problem; that of developing the elaborate and inefficient laboratory synthesis of cortisone to a point suitable for large-scale manufacture. Finally, all the synthetic analogues that did result from research on manufacturing processes were of diminished anti-inflammatory activity. One of the earliest examples is illustrative of the course of the search for better processes. In the course of efforts to find more satisfactory means of * Merck Sharp & Dohme Division of Merck & Co., Inc., Philadelphia, Pa. t Detailed treatments of the various phases of this subject are available?*

The impact of natural product research on drug discovery

Let me begin by simply telling you how honored I feel to be invited do address this illustrious audience. It has now been 5 years since the National Economic Development Office (NEDO) report first appeared. The latter, as you know, was bold enough to suggest that, pound for pound, investment in pharmaceutical innovation was twice as efficient in the U.K. as it was in the US. At the time of reading that report, my feelings — perhaps rooted in bicentennial patriotism — were those of doubt and incredulity. Since then, I — and many others I’m sure — have become mightily impressed with the brilliant contributions of the pharmaceutical sciences which continue to emanate from this country.