Tri- and Tetracyclic SERMs

Phenantrenes SignalGene reported on phenantrenes as SERM-type ligands for the ERs [180]. Most of the phenantrenes disclosed showed very low affinity for either ER, but dihydrophenantrene analog 143 showed reasonable ERa affinity (K, = 9 nM) and 22-fold ERa selectivity. 

Tetracyclic Benzothiophenes and Benzanthracenes Lilly disclosed conformationally restricted raloxifene and benzopyrane analogs [181]. Both series yielded tetracyclic SERM-type estrogens that showed good affinity for ERa. Benzothiophene 144 and benzopyrane 14S effectively inhibited MCF-7 proliferation. Compound 14S (LY-357489) showed high efficacy on bone protection and cholesterol metabolism at doses as low at lOmg/kg/day. No development has been reported. 

Lilly also disclosed two series of conformationally restricted benzanthracene derivatives [185]. These tetracyclic compounds showed high ERa affinity, but subtype selectivity was modest. Thus, benzothiophene analog 149 expressed 5-fold preference for ERa and similar ERa selectivity was noted for benzanthracene analog 150. The latter compound showed high MCF-7 antagonistic activity, whereas analog 149 was 20-fold less active. 

Steroidal SERM-Type Antagonists Several steroidal ER antagonists have been described in the literature. It was established that attachment of a side-chain to the 11- or 7-position of 17(5E2 or 17P-ethinyl-estradiol converts the molecules from agonists into antagonists. Aventis Pharma (formerly Hoechst Marion Roussel) disclosed 17PE2 and 17P-ethinyl-estradiol analogs having a SERM-type BSC attached to the 

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