Diaryl-Ethylenes, Imidazoles, Isoxazoles and Thiophenes

Imidazoles and Isoxazoles Pfizer reported an imidazole and an isoxazole as ERP-selective ligands [74], Imidazole 12 showed 27-fold ERp selectivity. Isoxazole 13 displayed higher ERp affinity, but in this case ERp selectivity was modest. 

Thiophene-1 -Carboxaldehydes Wyeth explored a set of thiophenes as new ligands for the ERs and it turned out that all compounds displayed preference for ERp [53]. Both phenolic functions were required for ER affinity and it was established that the 1-carboxaldehyde moiety significantly contributed to ERp selectivity. While replacement of the aldehyde functionality by a nitrile was well tolerated, conversion into an 

Biphenyls Wyeth reported a series of simple hydroxyl-biphenyls [60]. It was found that biphenyls bearing a 4 -carbaldehyde and one or more substituents ortho to the carbaldehyde moiety led to ER ligands (e.g. 18) with acceptable ER 3 affinity and good ER 3 selectivity. Attachment of a carbaldehyde oxime moiety gave 19 which showed enhanced ERP affinity [61]. This result suggests a favorable interaction between oximes and His475 in E R[3. Attachment of fluorine ortho to the hydroxyl group had a beneficial effect on ER 3 selectivity. Combination of the structure-affinity/selectivity relationship provided compound 20 that showed the best compromise between affinity and selectivity. 

Naphthalenes Wyeth extended its work on biphenyls to 1-phenyl-naphthyls. These investigations resulted in the identification of compound 21 which showed excellent ER i affinity and 50-fold ERf3 selectivity. The investigators further examined replacement of the naphthyl moiety by indoles, benzothiophenes and benzofurans [62]. It was found that many of these analogs still exhibit good ERP affinity (e.g. benzofurans 22). However, ERP selectivity was generally less pronounced. A positive exception was indole 23 which showed 37-fold ERP selectivity. 

A logical next step was the investigations of 2-phenyl-naphthalenes [63]. The archetype structure 24 already showed 13-fold ERp selectivity. Substituents were incorporated at different positions and it was found that specific substitutions at C4 (e.g. 26) or C8 (e.g. 25) resulted in significantly improved ERP selectivity. Substituent 

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