Fast follower approaches

Observations in connection with the administration of high doses of sulfanilamide as an antibacterial agent showed that the drug could produce alkaline urine and metabolic acidosis (accumulation of acid in the body). In 1940, T. Mann and D. Keilin [67h] at the University of Cambridge discovered that sulfanilamide inhibits carbonic anhydrase - an enzyme that catalyzes the decomposition of carbonic acid into carbonic anhydride and water. The secondary sulfonamides SO2NHR are not carbonic anhydrase inhibitors. In 1945, R. Pitss and R.S. Alexander at Cornell University (Ithaca, New York) used sulfanilamide to study renal 

and HCOs , and a rise in urine pH (alkaline urine). The possible relationships between pAa and carbonic anhydrase inhibitory potency led R. Robin and J. Clapp (Lederle Laboratories) [68] to prepare a series of acidic sulfonamides by introducing SO2NH2 groups in heterocyclic electron-withdrawing systems. 

Some of the synthetized compounds were found 2500 times more active than sulfanilamide. One of these, 2-acetylammo-l,3,4-thiadiazol-5-sulfonamide, acet-azolamide (Diamox ), was studied in detail and reported in 1954 by T. Maren, and became the first clinically effective carbonic anhydrase inhibitor-type diuretic [69]. 

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Having said all this, a recent report from a major pharmaceutical company with one of the largest reported screening collections revealed that just over 50% of their current lead optimization efforts invoke a "fast follower" approach [114]. Why is this One might speculate that as most companies work on the same targets these days chemists find it easier to "patent bust" than wait for the results of an HTS campaign which may take months to develop. Possibly, when more novel targets are identified, HTS of enhanced collections will deliver upon the promise that they hold. 

Competitive Intelligence-based Lead Generation and Fast Follower Approaches... 

Figure 8.8 Sulfanilamide-based fast follower approaches have led to a number of important drugs in various therapeutic areas.

The development of proton pump inhibitors (PPIs) for the treatment of gastric acid-related disorders is also one good example of how fast follower approaches can efficiently and effectively discover and develop compounds that allow newcomers to gain the market share in a given therapeutic area quickly. 

In summary, the omeprazole-based fast follower approaches identified key liabilities associated with omeprazole and put forward medicinal chemistry and formulation strategies to address these potential liabilities. The tactics used in addressing these points involved the following ... 

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