Glucocorticoid drug discovery

Fig. 14.4 Pharmacophore-based database searching for drug discovery. This example is based on a glucocorticoid receptor dataset (Morgan et al., 2002).

In addition to the examples discussed above, the structures of many clinically and biologically important proteins have been determined. Some of these are amenable to immediate use in drug discovery efforts. These include enzymes such as dihydrofolate reductase (Jansy, 1988), and thymidilate synthase (Appelt et al, 1991) both of which are involved in the synthesis of DNA precursors. Their inhibition is a target in anticancer chemotherapies. Structures of other proteins such as cAMP-dependent protein kinase, acetylcholinesterase, and the glucocorticoid receptor add to the knowledge base that will open new avenues... 

An example of Ellman s methodology as applied to a chiral reduction has been described in a drug discovery programme undertaken by Merck to develop selective non-steroidal glucocorticoid receptor agonists such as 243. Ketone 238 was converted to ketimine 239 by reaction with (i )-(-l-)-tert-butanesulfinamide and titanium tetraethoxide. Asymmetric reduction was effected by treatment with sodium borohydride followed by deprotection under acidic conditions to afford amine 242. The chiral product was subsequently converted to glucocorticoid receptor agonist 243 (Scheme 14.80). 

Inflammatory processes are mainly (78% of cases) treated with drugs. Until 1971, glucocorticoids with anti-inflammatory activity were the only drugs used, in spite of their strong secondary effects. The discovery in 1971 of the nonsteroidal anti-inflammatory drugs [2] was the impetus for the development of new anti-inflammatory drugs without secondary effects. Three main chemical structures, shown in Fig. 1, produce inhibition of the synthesis of prostaglandins in a wide variety of cells and tissues [3] ... 

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