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 dihydronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor α antagonist identified from this series...

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Published in:European journal of medicinal chemistry 2023-12, Vol.261, p.115821-115821, Article 115821
Main Authors: Al Noman, Md Abdullah, Cuellar, Rebecca A.D., Kyzer, Jillian L., Chung, Sanny S.W., Cheryala, Narsihmulu, Holth, Trinh A.D., Maitra, Soma, Naqvi, Tahmina, Wong, Henry L., Schönbrunn, Ernst, Hawkinson, Jon E., Wolgemuth, Debra J., Georg, Gunda I.
Format: Article
Language:English
Subjects:
Animals
Benzopyrans - pharmacology
Contraception
Male
Male contraception
Mice
Retinoic acid receptor alpha
Retinoic Acid Receptor alpha - metabolism
Selectivity
Structure-activity relationships
Testis
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Summary:Reported here are the synthesis and in vitro evaluation of a series of 26 retinoic acid analogs based on dihydronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor α antagonist identified from this series. In vitro evaluation indicated that 21 has favorable physicochemical properties and a favorable pharmacokinetic PK profile in vivo with significant 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. [Display omitted] •Synthesis and evaluation of 26 retinoic acid receptor antagonists for potency and selectivity.•Chromene analog 21 was the most potent and selective RARα antagonist identified.•Compound 21 inhibited of spermatogenesis but was not effective in mating studies.•Amides had best potency and selectivity. Reversed amides, urea and sulfonamides were inactive.•Compounds 3 and 6 with small antagonist pocket groups (phenyl, thiophene) are selective agonists for RARβ.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2023.115821