Male contraceptive development: A medicinal chemistry perspective

Norcross, Neil R.; Georgiou, Irene; Johnston, Zoe C; Gruber, Franz S; Swedlow, Jason R.; Read, Kevin D.; Barratt, Christopher L.R.; Gilbert, Ian H.

doi:10.1016/j.ejmech.2022.114709

Cited by 9 publications

(6 citation statements)

References 95 publications

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“…In parallel, a deeper understanding of sperm maturation, motility, fertilization, and possible interventions for male infertility is required to counter declining birth rates. Recently, the application of advanced technologies has helped move the human fertility field forward, revealing new potential targets for both contraception and fertility, and new compounds as contraceptive candidates (reviewed by [ 1 – 3 ]). A key part of this effort is the development of mechanistic insight and drug candidates that affect the behaviour and properties of human spermatozoa [ 4 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Sperm Toolbox—A selection of small molecules to study human spermatozoa

Gruber,

Richardson,

Johnston

et al. 2024

PLoS ONE

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Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.

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Section: Introductionmentioning

confidence: 99%

Sperm Toolbox—A selection of small molecules to study human spermatozoa

Gruber,

Richardson,

Johnston

et al. 2024

PLoS ONE

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“…Other strategies focus on non-hormonal targets identified as essential for spermatogenesis via gene distruption technologies. Among the most advanced of these efforts, a small molecule inhibitor against bromodomain testes-specific protein reversibly suppressed spermatogenetis in mice 10 , but it remains unclear whether the testis-specific isoform can be selectively inhibited 11 . Similarly, a retinoic acid receptor antagonist rendered mice reversibly sterile by blocking sperm production 12 , but because retinoic acid receptors have other functions 13 , there are concerns that chronic use may lead to undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

On-demand male contraception via acute inhibition of soluble adenylyl cyclase

et al. 2023

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Nearly half of all pregnancies are unintended; thus, existing family planning options are inadequate. For men, the only choices are condoms and vasectomy, and most current efforts to develop new contraceptives for men impact sperm development, meaning that contraception requires months of continuous pretreatment. Here, we provide proof-of-concept for an innovative strategy for on-demand contraception, where a man would take a birth control pill shortly before sex, only as needed. Soluble adenylyl cyclase (sAC) is essential for sperm motility and maturation. We show a single dose of a safe, acutely-acting sAC inhibitor with long residence time renders male mice temporarily infertile. Mice exhibit normal mating behavior, and full fertility returns the next day. These studies define sAC inhibitors as leads for on-demand contraceptives for men, and they provide in vivo proof-of-concept for previously untested paradigms in contraception; on-demand contraception after just a single dose and pharmacological contraception for men.

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“…[ 1 ] In addition, nonhormonal contraceptive agents are currently being discovered and developed. [ 2,3 ] One such approach is focused on retinoic acid signaling. [ 4 ] The importance of vitamin A for normal sperm development was first noted in 1925 when it was observed that rats placed on a vitamin A deficient (VAD) diet were infertile.…”

Section: Introductionmentioning

confidence: 99%

“…3 and extracted three times with EtOAc. The combined organic extracts were dried using Na 2 SO 4 , before being condensed under reduced pressure.…”

mentioning

confidence: 99%

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

Kyzer

Noman

Cuellar

et al. 2023

Archiv der Pharmazie

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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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Male contraceptive development: A medicinal chemistry perspective

Cited by 9 publications

References 95 publications

Sperm Toolbox—A selection of small molecules to study human spermatozoa

Sperm Toolbox—A selection of small molecules to study human spermatozoa

On-demand male contraception via acute inhibition of soluble adenylyl cyclase

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

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