Investigation of selective retinoic acid receptor alpha antagonist ER-50891 and related analogs for male contraception

Retinoic acid receptor alpha (RAR alpha) antagonist ER-50891 and 15 analogs were prepared and tested in vitro for potency and selectivity at RAR alpha, RAR beta, and RAR gamma using transactivation assays. Minor modifications to the parent molecule such as the introduction of a C4 tolyl group in place of the C4 phenyl group on the quinoline moiety slightly increased the RAR alpha selectivity but larger substituents significantly decreased the potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond produced inactive compounds. ER-50891 was found to be stable in male mouse liver microsomes and was tested in male mice to assess its effects on spermatogenesis. Characteristic, albeit modest and transient, effects on spermatogenesis were observed.

Automated summary

Retinoic acid receptor alpha (RAR alpha) antagonist ER-50891 and its 15 analogs were studied for their potency and selectivity at RAR alpha, RAR beta, and RAR gamma in vitro. Minor modifications to the parent molecule, such as introducing a C4 tolyl group instead of the C4 phenyl group on the quinoline moiety, slightly increased the selectivity for RAR alpha, while larger substituents significantly decreased potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond resulted in inactive compounds. ER-50891 was stable in male mouse liver microsomes and its effects on spermatogenesis were observed in male mice, showing characteristic albeit modest and transient effects.