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    noman@stanford.edu
    University - Scholar Department: Stanford Cancer Institute Core Position: Postdoctoral Scholar

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  • From Discovery to Clinical Trial: YCT-529, an Oral NonHormonal Male Contraceptive Targeting the Retinoic Acid Receptor Alpha JOURNAL OF MEDICINAL CHEMISTRY Shi, R., Al Noman, M., Mannowetz, N., Cheryala, N., Haque, E., Maitra, S., Naqvi, T., Chung, S. S. W., Bakshi, A., Hawkinson, J. E., Wong, H. L., Wolgemuth, D. J., Georg, G. I. 2026

    Abstract

    The retinoic acid receptor alpha (RARα) has emerged as a compelling genetically and pharmacologically validated target for nonhormonal male contraception due to its essential role in spermatogenesis. In the present study, a search for specific inhibitors of RARα utilized systematic linker bioisosterism, hydrophobic core modification, and iterative structure-activity relationship refinement, identified the acid 9, a pyrrole-linked analog that potently inhibits RARα (IC50 = 1.2 nM) with >300-fold selectivity over RARβ and RARγ. Sprague-Dawley rat studies with the sodium salt of 9, YCT-529, showed good oral bioavailability and dose-proportional pharmacokinetics without drug accumulation after 28 days of dosing. Once-daily oral administration (0.75 mg/kg for 28 days) reversibly suppressed epididymal sperm counts and fertility in rats, with a no-observed-adverse-effect level at 30 mg/kg (highest dose tested), affording a ≥40-fold therapeutic window. These findings validated aromatic linker substitution as a powerful design strategy for identifying RARα antagonists and led to the clinical advancement of YCT-529 as a nonhormonal male contraceptive.

    View details for DOI 10.1021/acs.jmedchem.5c03051

    View details for Web of Science ID 001660633500001

    View details for PubMedID 41524264

https://orcid.org/0000-0002-2980-0592