SERM-type estrogens

Pyrazolopyrimidines Transformation of the agonist into a SERM-type estrogen was attempted by attaching BSCs to the 2- or 3-p-hydroxyphenyl group [139]. Modest ER affinity and 4-fold ER(3 selectivity was observed for analog 106. Compound 106 antagonized 17[3E2-induced transcriptional activity in HEC-1 cells. 

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. 

From the benzoxathiins reported thus far, 117 exhibits good prospects for further development. The optimized BSC was also tested on other SERM-type ligands, including raloxifene, bazedoxifene and lasofoxifene [151]. Although some increase in ER affinity was observed, no improvement in the rat uterine profile was observed. This result indicates that the optimized side-chain from the benzoxathiins series is not easily transferable to other estrogen ligands. 

DEPENDING ON THE CELL TYPE ON THE ESTROGEN-DEPENDENT GENE The synthesis of messenger-RNA induced by each SERM is ... 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

Pure antiestrogens are distinguishable form other SERMs in terms of their mechanism of action, although both classes of agent mediate their effects through the two types of estrogen receptors (ERa and ER/J). 

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