ERa-Selective Antagonists

Pyrazoles and Isoxazoles Consistent with the finding that certain pyrazoles exhibit ERa-selective agonism, the University of Illinois reported that attachment of a BSC to these pyrazoles provided ERa-selective antagonists [171, 172]. Thus, 220-fold ERa selectivity was observed for pyrazole 137 (methyl-piperidino-pyrazole). It was found that the combination of a methyl group at C4 and piperidine as part of the BSC were key elements that direct ERa selectivity. Although larger alkyl groups had little effect... 

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. 

Levesque. L. etai (1991) The interaction of 3.5-pyrazolidinedione drugs with receptors for f-Met-Leu-Phe on human neutrophil leukocytes a study of the structure- activity relationship. Can. J. Physiol. Pharmacol., 69,419-425. Levesque. L. era (1992) Comparison of two classes of non-peptide drugs as antagonists of neutrophil receptors for f-Met-Leu-Phe. Pyrazolons and iodinated radiographic contrast agents. Biochem. Pharmacol., 43. 553-560. Derian. C.K. er at (1996) Selective inhibition of N-formylpeptide-induced neutrophil activation by carbamate-modified peptide analogues. Biochemistry, 35.1265-1269. 

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