Isosteric Substitution in the Design of Safer Drug Substances

Isosteric Substitution in the Design of Safer Drug Substances 

Medicinal chemists have used isosterism for the design of safe, effective drug substances for many years. During the development of anti-ulcer medications, for example, it was found that metiamide (38) greatly reduced acid secretion in the gastrointestinal tract by antagonizing H2-receptor sites. Its potential as auseful anti-ulcer medication was lessened by adverse effects caused by the thiourea moiety, a toxicophore (Table 4.1). This moiety is essential for H2-receptor blockade, but bestows toxicity. 

Isosteric replacement of the thiourea moiety with the cyanoguanidine moiety gave cimetidine (39), a potent H2-receptor antagonist that lacks the toxicity of 38. Cimet-idine is a widely used anti-ulcer medication because of its effectiveness in treating ulcers and relative safety. It is noteworthy that in this example, this isosteric modification selectively reduced toxicity without affecting pharmacological activity. 

This is a main reason why isosteric substitution has for many years been a common practice among medicinal chemists for the design of clinically efficacious drug products. Many other examples of the use of isosterism in drug design can be found in the literature [68-72]. 

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