Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception

Reported here are the synthesis and in vitro evaluation of a series of 26 retinoic acid analogs based on dihy-dronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor alpha antagonist identified from this series. In vitro evaluation indicated that 21 has favorable physicochemical properties and a favorable pharmacokinetic PK profile in vivo with sig-nificant oral bioavailability, metabolic stability, and testes exposure. Compound 21 was evaluated for its effects on spermatogenesis and disruption of fertility in a mouse model. Oral administration of compound 21 at low doses showed reproducibly characteristic albeit modest effects on spermatogenesis, but no effects on fertility were observed in mating studies. The inhibition of spermatogenesis could not be enhanced by raising the dose and lengthening the duration of dosing. Thus, 21 may not be a good candidate to pursue further for effects on male fertility.

Automated summary

A series of retinoic acid analogs based on dihydronaphthalene and chromene scaffolds were synthesized and evaluated in vitro. Compound 21, a chromene amide analog, was identified as the most potent retinoic acid receptor alpha antagonist with favorable physicochemical properties and pharmacokinetic profile. In a mouse model, compound 21 showed modest effects on spermatogenesis at low doses, but did not impact fertility. Further investigation on its effects on male fertility may not be warranted.