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Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception.
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.
Afiliación
  • Al Noman MA; 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.
  • Cuellar RAD; 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.
  • Kyzer JL; 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.
  • Chung SSW; Department of Genetics and Development, USA.
  • Cheryala N; 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.
  • Holth TAD; 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.
  • Maitra S; 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.
  • Naqvi T; 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.
  • Wong HL; 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.
  • Schönbrunn E; Department of Drug Discovery, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.
  • Hawkinson JE; 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.
  • Wolgemuth DJ; 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.
  • Georg GI; 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: georg@umn.edu.
Eur J Med Chem ; 261: 115821, 2023 Dec 05.
Article en En | MEDLINE | ID: mdl-37776573
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Testículo / Anticoncepción Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
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PubMed Links
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Testículo / Anticoncepción Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos