Hn O

FIGURE 3.22 Metabolism of 667-coumate.

rapidly disappears from plasma because of its low stability, presumably due to the facile E1cB elimination of sulfamate to give the corresponding coumarin (Fig. 3.22), but it shows a long half-life in blood. This increased stability has been ascribed to binding of the drug to carbonic anhydrase II in erythrocytes. The hydrophobic environment in which the coumarin ring system is bound according to modeling studies explains the enhanced stability, since it hampers the generation of charged intermediates through the E1cB mechanism.35

Further research in this area is focused toward the development of nonestro-genic steroidal inhibitors of sulfatase by structural manipulation of the A or D rings. Another current goal is the development of dual aromatase-sulfatase inhibitors, which is being pursued by the introduction of the critical sulfamate unit in structures with known aromatase-inhibiting properties. In this connection, it is interesting to note that 667 Coumate shows some activity as an aromatase inhibitor.33

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