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

Md Abdullah Al Noman; Rebecca A.D. Cuellar; Jillian L. Kyzer; Sanny S.W. Chung; Narsihmulu Cheryala; Trinh A.D. Holth; Soma Maitra; Tahmina Naqvi; Henry L. Wong; Ernst Schönbrunn; Jon E. Hawkinson; Debra J. Wolgemuth; Gunda I. Georg

doi:10.1016/j.ejmech.2023.115821

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

Md Abdullah Al Noman, Rebecca A.D. Cuellar, Jillian L. Kyzer, Sanny S.W. Chung, Narsihmulu Cheryala, Trinh A.D. Holth, Soma Maitra, Tahmina Naqvi, Henry L. Wong, Ernst Schönbrunn, Jon E. Hawkinson, Debra J. Wolgemuth, Gunda I. Georg

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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.

Original language	English (US)
Article number	115821
Journal	European Journal of Medicinal Chemistry
Volume	261
DOIs	https://doi.org/10.1016/j.ejmech.2023.115821
State	Published - Dec 5 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Masson SAS

Keywords

Male contraception
Retinoic acid receptor alpha
Selectivity
Structure-activity relationships

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2023.115821

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Al Noman, M. A., Cuellar, R. A. D., Kyzer, J. L., Chung, S. S. W., Cheryala, N., Holth, T. A. D., Maitra, S., Naqvi, T., Wong, H. L., Schönbrunn, E., Hawkinson, J. E., Wolgemuth, D. J., & Georg, G. I. (2023). Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception. European Journal of Medicinal Chemistry, 261, Article 115821. https://doi.org/10.1016/j.ejmech.2023.115821

Al Noman, MA, Cuellar, RAD, Kyzer, JL, Chung, SSW, Cheryala, N, Holth, TAD, Maitra, S, Naqvi, T, Wong, HL, Schönbrunn, E, Hawkinson, JE, Wolgemuth, DJ & Georg, GI 2023, 'Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception', European Journal of Medicinal Chemistry, vol. 261, 115821. https://doi.org/10.1016/j.ejmech.2023.115821

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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.",

keywords = "Male contraception, Retinoic acid receptor alpha, Selectivity, Structure-activity relationships",

author = "{Al Noman}, {Md Abdullah} and Cuellar, {Rebecca A.D.} and Kyzer, {Jillian L.} and Chung, {Sanny S.W.} and Narsihmulu Cheryala and Holth, {Trinh A.D.} and Soma Maitra and Tahmina Naqvi and Wong, {Henry L.} and Ernst Sch{\"o}nbrunn and Hawkinson, {Jon E.} and Wolgemuth, {Debra J.} and Georg, {Gunda I.}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Masson SAS",

year = "2023",

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doi = "10.1016/j.ejmech.2023.115821",

language = "English (US)",

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AU - Al Noman, Md Abdullah

AU - Cuellar, Rebecca A.D.

AU - Kyzer, Jillian L.

AU - Chung, Sanny S.W.

AU - Cheryala, Narsihmulu

AU - Holth, Trinh A.D.

AU - Maitra, Soma

AU - Naqvi, Tahmina

AU - Wong, Henry L.

AU - Schönbrunn, Ernst

AU - Hawkinson, Jon E.

AU - Wolgemuth, Debra J.

AU - Georg, Gunda I.

PY - 2023/12/5

Y1 - 2023/12/5

N2 - 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.

AB - 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.

KW - Male contraception

KW - Retinoic acid receptor alpha

KW - Selectivity

KW - Structure-activity relationships

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JO - European Journal of Medicinal Chemistry

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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