biostudies-literatureShi RMale Contraceptive InitiativeYourChoice TherapeuticsNational Institute of Child Health and Human Development1568-1605https://www.ebi.ac.uk/biostudies/studies/S-EPMC12833862biostudies-literatureUnknown69(2)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 Journal of medicinal chemistryFrom Discovery to Clinical Trial: YCT-529, an Oral NonHormonal Male Contraceptive Targeting the Retinoic Acid Receptor Alpha.PMC128338625P50HD093540HHSN275201300017CAl Noman MAShi RHawkinson JEChung SSWBakshi AMannowetz NGeorg GIWong HLHaque EMaitra SCheryala NWolgemuth DJNaqvi TfalseFrom Discovery to Clinical Trial: YCT-529, an Oral NonHormonal Male Contraceptive Targeting the Retinoic Acid Receptor Alpha.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 2026-01-01T00:00:00Z2026 Jan2026-06-09T07:21:00.425Z2026-06-09T03:12:00.416ZS-EPMC128338624152426410.1021/acs.jmedchem.5c03051