Drug design/development isosteres

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. 

The design of enzyme inhibitors has included random screening of synthetic chemical agents, natural products, and combinatorial libraries followed by molecular optimization or structure-activity relationships of so-called lead structures as well as bio-isosteric analogues of the enzyme substrates themselves. Drugs (e.g., finasteride) also have been developed for one indication but, based on observed side effects, have lead to other uses. 

One of the successful examples of employment of QSAR in the design and development of an HIV drug is the discovery of Indinavir (L-735,524) (2), one of the first HIVPI approved by the US-FDA. Holloway et aL [163] first reported this compound when they conducted SAR studies on a combined series of isostere derivatives of (43,44). A high correlation between the inter-molecular interaction energy ( int) calculated for HIVPR inhibitor complexes and enzyme inhibition activity was observed. QSAR 51-53 were developed for native, acetylpepstatin-inhibited and L-689,502-inhibited HIVPR, respectively [ 163]. X-ray coordinates and the force field technique were employed in the calculation of int (intermolecular interaction energy). In these QSAR, rev is the cross-validated correlation coefficient. 

---