Stability to Conjugation Processes

Conjugation with glucuronic acid or sulphate requires a nucleophilic substituent to be present in the molecule, normally an hydroxyl function. In the case of the glu-

curonyl transferases this can be phenol, primary, secondary or even tertiary alcohol or carboxylate or in the case of sulphotransferases, normally phenol. In some cases primary alcohols can also form sulphate conjugates. The most "reactive" grouping is the phenol and a simple rule is to eliminate such groupings unless essential for activity. In some cases bioisosteres can be introduced to retain pharmacological activity and overcome conjugation. To act as agonists of the dopamine receptor an H-bond donor group is essential in the correct position on a phenyl ring whose centre is situated 5.1 A from a protonated nitrogen atom [23]. Figure 7.24 illustrates 7-hydroxy-(amino) tetralin analogues which are potent agonists.

These compounds have very low bioavailability and short duration due to extremely rapid glucuronidation [24]. Substitution of the phenolic hydroxy group with a pyrrolo ring (Figure 7.20) gives a series of compounds with a suitable H-bond donor in the correct position (also the geometry matches that of the phenolic hydroxyl), but resistant to glucuronidation [23]. It is not sufficient to replace functionality with

Fig. 7.24 Substitution of a pyrrolo for a phe-

receptor interactions but is resistant to glucuronidation.


Fig. 7.25 Design of beta-2 selective adrenoceptor agonists resistant to catechol O-methyl transferase (COMT).

Fig. 7.25 Design of beta-2 selective adrenoceptor agonists resistant to catechol O-methyl transferase (COMT).

7.8 Pharmacodynamics and Conjugation | 95

groupings with similar chemical properties. For instance tetrazolyl is almost an exact mimic of the carboxyl group and readily undergoes glucuronidation.

Catechol methyl transferases require the catechol function to be present to bind to the Mg2+ ion. In the search for p2-adrenoceptor selectivity to produce potent bron-chodilators with low cardiovascular effects, changing the 3,4-hydroxy grouping of the catechol to 3,5- or 3-hydroxyl, 4-methyl-hydroxy, proved to be important (Figure 7.25). These compounds now have much improved bioavailability and pharmacokinetics due to their resistance to catechol methyl transferases.

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