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

Mice Animals Male Retinoic Acid Receptor alpha / metabolism Testis Contraception Benzopyrans / pharmacology
Male contraception Retinoic acid receptor alpha Selectivity Structure-activity relationships

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
05 Dec 2023
Historique:
received: 23 07 2023
revised: 12 09 2023
accepted: 13 09 2023
medline: 3 11 2023
pubmed: 1 10 2023
entrez: 30 9 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ejmech.2023.115821 PMID: 37776573
pubmed: 37776573
pii: S0223-5234(23)00788-2
doi: 10.1016/j.ejmech.2023.115821
pii:
doi:

Substances chimiques

compound 21 RC2V4W0EYC
Retinoic Acid Receptor alpha 0
Benzopyrans 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

115821

Informations de copyright

Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Md Abdullah 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.

Rebecca A D 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.

Jillian L 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.

Sanny S W Chung (SSW)

Department of Genetics and Development, USA.

Narsihmulu 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.

Trinh A D 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.

Soma 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.

Tahmina 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.

Henry L 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.

Ernst Schönbrunn (E)

Department of Drug Discovery, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.

Jon E 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.

Debra J 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.

Gunda I 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Strategies for developing retinoic acid...
questionsmedicales.fr › Eucaryotes › Animaux › Strategies for developing retinoic acid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Récepteurs à l'acide rétinoïque › Récepteur alpha de l'acide rétinoïque › Strategies for developing retinoic acid...
questionsmedicales.fr › Système endocrine › Glandes endocrines › Gonades › Testicule › Strategies for developing retinoic acid...
questionsmedicales.fr › Thérapeutique › Contraception › Strategies for developing retinoic acid...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzopyranes › Strategies for developing retinoic acid...