Optimizing the Selectivity of Nonselective Lead Structures

Medicinal chemists always followed and still apply the principle of chemical and biological similarity. Whenever they discover an active lead, they modify its chemical structure more or less systematically, to find similar analogs with improved activities, selectivities, ADME (absorption, distribution, metabolism, elimination) properties fewer side effects and less toxic properties. However, as discussed above, structurally closely related analogs may have significantly different specificity or even a completely different mode of action. 

53 shows a greater than 300-fold selectivity for the 5-HT3 receptor, as compared to the 5-HT4 receptor, whereas 54 is at least three orders of magnitude more active at the 5-HT4 receptor than at the 5-HT3 receptor. 

The closely related compound 55 is an orally active antitussive drug. 

Despite their close chemical relationship, the benzimidazole carboxamides 53 and 

Compound sstT sst2 sst3 sst4 sstS 

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