2. Academic Validation
  3. Development of a Second-Generation RARα Selective Antagonist as an Orally Bioavailable, Effective, Safe, and Reversible Male Contraceptive

Development of a Second-Generation RARα Selective Antagonist as an Orally Bioavailable, Effective, Safe, and Reversible Male Contraceptive

  • J Med Chem. 2026 May 28;69(10):12144-12170. doi: 10.1021/acs.jmedchem.6c00011.
Rui Shi 1,  Kristen John 1,  Xuan Qin 2,  Ehfazul Haque 1,  Taimeng Liang 3,  Narsihmulu Cheryala 1,  Feng Li 2,  Henry L Wong 1,  Gunda I Georg 1
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, Minnesota 55414, United States.
  • 2 Center for Drug Discovery, Department of Pathology and Immunology, NMR and Drug Metabolism Core, Advanced Technology Cores, Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, One Baylor Plaza, MS: BCM330, Houston, Texas 77030, United States.
  • 3 Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, Minnesota 55455-0431, United States.
PMID: 42112580 DOI: 10.1021/acs.jmedchem.6c00011
Abstract

We report the design and SAR studies of benzopyran-, benzofuran-, and benzothiophene-derived inhibitors of the retinoic acid receptor alpha (RARα) for male contraception. SAR studies identified critical features influencing activity, such as the optimal positioning of antagonism moieties and substituents, leading to the discovery of (S)-4-(5-(2,8-dimethyl-5-(p-tolyl)-2H-chromen-3-yl)-1H-pyrrol-2-yl)benzoic acid (compound 23). Compound 23 is a highly potent RARα inhibitor (IC50 = 0.051 nM) with excellent selectivity (>1650-fold over RARβ and >1960-fold over RARγ) and ADMET properties. Compound 23 is orally bioavailable and reduces sperm counts in mice for a full male contraceptive effect with a minimum effective dose between 0.3 and 1 mg/kg/day, with complete recovery after drug continuation. Using imaging mass spectrometry, we analyzed the spatial distribution of compound 23 in mouse seminiferous tubules. Compound 23 does not cross the blood-testis barrier and therefore must exert its activity during the initial phases of spermatogenesis.

Figures
Products