2. Academic Validation
  3. Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception

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

  • Eur J Med Chem. 2023 Sep 25:261:115821. doi: 10.1016/j.ejmech.2023.115821.
Md Abdullah Al Noman 1,  Rebecca A D Cuellar 1,  Jillian L Kyzer 1,  Sanny S W Chung 2,  Narsihmulu Cheryala 1,  Trinh A D Holth 1,  Soma Maitra 1,  Tahmina Naqvi 1,  Henry L Wong 1,  Ernst Schönbrunn 3,  Jon E Hawkinson 1,  Debra J Wolgemuth 4,  Gunda I Georg 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN, 55414, USA.
  • 2 Department of Genetics and Development, USA.
  • 3 Department of Drug Discovery, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.
  • 4 Department of Genetics and Development, USA; Department of Obstetrics and Gynecology, USA; The Institute of Human Nutrition, USA; The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
  • 5 Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN, 55414, USA. Electronic address: [email protected].
PMID: 37776573 DOI: 10.1016/j.ejmech.2023.115821
Abstract

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.

Keywords

Male contraception; Retinoic acid receptor alpha; Selectivity; Structure-activity relationships.

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