Investigation of selective retinoic acid receptor alpha antagonist ER-50891 and related analogs for male contraception

Jillian L. Kyzer; Md Abdullah Al Noman; Rebecca A Cuellar; Sanny S.W. Chung; Soma Maitra; Tahmina Naqvi; Jon Hawkinson; Debra J. Wolgemuth; Gunda I. Georg

doi:10.1002/ardp.202300031

Investigation of selective retinoic acid receptor alpha antagonist ER-50891 and related analogs for male contraception

Jillian L. Kyzer, Md Abdullah Al Noman, Rebecca A Cuellar, Sanny S.W. Chung, Soma Maitra, Tahmina Naqvi, Jon Hawkinson, Debra J. Wolgemuth, Gunda I. Georg

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Abstract

Retinoic acid receptor alpha (RARα) antagonist ER-50891 and 15 analogs were prepared and tested in vitro for potency and selectivity at RARα, RARβ, and RARγ using transactivation assays. Minor modifications to the parent molecule such as the introduction of a C4 tolyl group in place of the C4 phenyl group on the quinoline moiety slightly increased the RARα selectivity but larger substituents significantly decreased the potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond produced inactive compounds. ER-50891 was found to be stable in male mouse liver microsomes and was tested in male mice to assess its effects on spermatogenesis. Characteristic, albeit modest and transient, effects on spermatogenesis were observed.

Original language	English (US)
Article number	2300031
Journal	Archiv der Pharmazie
Volume	356
Issue number	7
DOIs	https://doi.org/10.1002/ardp.202300031
State	Published - Jul 2023

Bibliographical note

Funding Information:
Jillian L. Kyzer acknowledges support from NIH predoctoral training grant 5 T32 GM008700 and Md Abdullah Al Noman acknowledges a predoctoral fellowship from the Male Contraceptive Initiative. This work was supported by NICHD grants 1 U01 HD076542, P50 HD093540, and NICHD contract HHSN275201300017C.

Publisher Copyright:
© 2023 Deutsche Pharmazeutische Gesellschaft.

Keywords

inhibition
retinoic acid receptor alpha
selectivity
spermatogenesis
transactivation assays

PubMed: MeSH publication types

Journal Article

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abstract = "Retinoic acid receptor alpha (RARα) antagonist ER-50891 and 15 analogs were prepared and tested in vitro for potency and selectivity at RARα, RARβ, and RARγ using transactivation assays. Minor modifications to the parent molecule such as the introduction of a C4 tolyl group in place of the C4 phenyl group on the quinoline moiety slightly increased the RARα selectivity but larger substituents significantly decreased the potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond produced inactive compounds. ER-50891 was found to be stable in male mouse liver microsomes and was tested in male mice to assess its effects on spermatogenesis. Characteristic, albeit modest and transient, effects on spermatogenesis were observed.",

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note = "Funding Information: Jillian L. Kyzer acknowledges support from NIH predoctoral training grant 5 T32 GM008700 and Md Abdullah Al Noman acknowledges a predoctoral fellowship from the Male Contraceptive Initiative. This work was supported by NICHD grants 1 U01 HD076542, P50 HD093540, and NICHD contract HHSN275201300017C. Publisher Copyright: {\textcopyright} 2023 Deutsche Pharmazeutische Gesellschaft.",

year = "2023",

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doi = "10.1002/ardp.202300031",

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AU - Noman, Md Abdullah Al

AU - Cuellar, Rebecca A

AU - Chung, Sanny S.W.

AU - Maitra, Soma

AU - Naqvi, Tahmina

AU - Hawkinson, Jon

AU - Wolgemuth, Debra J.

AU - Georg, Gunda I.

N1 - Funding Information: Jillian L. Kyzer acknowledges support from NIH predoctoral training grant 5 T32 GM008700 and Md Abdullah Al Noman acknowledges a predoctoral fellowship from the Male Contraceptive Initiative. This work was supported by NICHD grants 1 U01 HD076542, P50 HD093540, and NICHD contract HHSN275201300017C. Publisher Copyright: © 2023 Deutsche Pharmazeutische Gesellschaft.

PY - 2023/7

Y1 - 2023/7

N2 - Retinoic acid receptor alpha (RARα) antagonist ER-50891 and 15 analogs were prepared and tested in vitro for potency and selectivity at RARα, RARβ, and RARγ using transactivation assays. Minor modifications to the parent molecule such as the introduction of a C4 tolyl group in place of the C4 phenyl group on the quinoline moiety slightly increased the RARα selectivity but larger substituents significantly decreased the potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond produced inactive compounds. ER-50891 was found to be stable in male mouse liver microsomes and was tested in male mice to assess its effects on spermatogenesis. Characteristic, albeit modest and transient, effects on spermatogenesis were observed.

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KW - retinoic acid receptor alpha

KW - selectivity

KW - spermatogenesis

KW - transactivation assays

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Investigation of selective retinoic acid receptor alpha antagonist ER-50891 and related analogs for male contraception

Abstract

Bibliographical note

Keywords

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