Table 2.
Development of nonhormonal male contraceptive
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| No | <Molecule target/mechanism of action | Small molecule of contraception candidate | Note | |||
| Name | Function | Name | Role | Response | ||
| WIN18.446 | Analog in the Retinoic acid (RA) pathway | Efficacious and well tolerated in inhibiting spermatogenesis (50) | It was halted because consuming alcohol while taking this drug results in a severe disulfiram reaction (51) | |||
| 1. | Retinoic acid | |||||
| receptor (RAR) | Inhibiting | |||||
| spermatogenesis | ||||||
| (50) | BMS-189453 | RAR antagonist | Reversible and inhibition of spermatogenesis in the mouse model (52) | Screening for a strong specific antagonist RAR using in silico method to inhibiting spermatogenesis (6) | ||
| 2. | Bromodomain, testis specific (BRDT) | Plays an important role in chromatin remodeling during spermatogenesis (53, 54) | JQ1 | BRDT inhibitor | Reversible contraceptive effect in male rats (55) but can Binds to other BRD proteins that do not target molecules (56) | It is necessary to develop optimized BRDT inhibitors. The potent and selective BET inhibitor candidate for BD2 was revealed by in silico analysis (6) |
| 3. | Kalium channel, subfamily U, member 1 (Kcnu1/Slo3) | Controls calcium influx through CatSper. SLO3 genetic deletion causes infertility in male mice (57) | RU1968 | Steroid inhibitor | CatSper progesterone-mediated motility dysfunction through Inhibition of hSLO3 (58) | It is unclear whether this approach would be more suitable for female use because of the impact on progesterone function in the fallopian tubes (58) |
| 4. | Epididymal peptidase inhibitor (EPPIN) | Sperm motility (31) | EP055 | EPPIN inhibitor | Significant reduction in sperm motility reduce through decreasing sperm internal pH and rapid calcium levels (59, 60) | Preclinical study |
| CDB-4022 | Mitogen-activated protein kinase (MAPK) pathway activation in Sertoli-germ cell junction | Inhibits the mature sperm (61) | Reversible decrease in sperm production with no apparent side effects (61) | |||
| 5. | Sertoli cell | Sperm maturation | ||||
| (61-63) | Indazole carboxylic acid derivatives such as Gamendazole, H2-gamendazole, and Adjudin | Disorder of Sertoli cell adhesive junction protein | In rats treated orally with fertility was inhibited by H2-gamendazole in rat (62) The effect is reversible at low-drug doses, and irreversible at higher doses. Adjudin was conjugated to the recombinant FSH binding fragment to specifically target the testicular germ cell-Sertoli germ cell junction (63) | |||
| 6. | Testis-specific serine/threonine kinases (TSSK) | Spermatogenesis and sperm function (53) | GSK2163632 A | TSSK2 inhibitor | Loss of fertility in mice (53) | It is necessary to identify selective molecules in inhibiting TSSK2 because this compound can inhibit other kinases than TSSK2. Inconsistent side effects was leaded by the nonselective action of this molecule (53) |
| 7. | CatSper | Capacitation, hyperactivation of motility, and the acrosome reaction (54) | Nifedipine | Calcium channel blocker (54) | Epididymal sperm counts, motility, and fertility of male BALB/c mice significantly decreased (54) | |
| Name | Function | Name | Role | Response | ||
| 8. | Vasopression receptor | Sperm count and motility (64) | Deamino [Cys 1, D-ArgS] vasopressin (dDAVP) | Vasopressin receptor (AVPR2) agonist (64) | Decreased intracellular pH, PKA substrates, sperm motility, and increased Ca2+ concentration (64) | |
| 9. | Actin-related protein 2/3 (Arp2/3) | Sperm motility and capacitation (65) | CK-636 | Arp2/3 complex antagonist | This molecule induced hyper-activated motility and acrosomal reaction, besides that spermatozoa were inhibited by intracellular calcium and tyrosine phosphorylation levels (65) | Reduced fertilization and embryo development in the highest concentration of CK-636, but after treatment, fertilization significantly increased, whereas embryonic development significantly decreased (65) |
| 10. | Na, K-ATPase (NKA) | Sperm motility (66) | Ouabain | Inhibitor of NKA activity (66) | Reduction in sperm motility (66) | |
| 11. | Ca-ATPase of the plasma membrane (PMCA) | Sperm motility (66) | Amiloride | Inhibitor of PMCA activity (66) | Reduction in sperm motility (66) | |
| 12. | Na(+)/Ca (2) (+)-exchanger (NCX) | Sperm motility (66) | Eosin | Inhibitor of NCX activity (66) | Reduction in sperm motility (66) | |
| 13. | Na(+)/H(+)-exchanger (NHE) | Sperm motility (66) | KB-R7943 | Inhibitor of NHE activity (66) | Reduction in sperm motility (66) | |
| 14. | Dynein-ATPase activity | Sperm motility (66) | Acidic pH and micromolar concentrations of Ca2+ | Inhibitor of Dynein-ATPase activity (66) | Inhibition of sperm motility through higher cytosolic H(+) and Ca (2) (+) (66) | |
| 15. | α1-adrenoceptor | Contribute to ejaculation (67) | Tamsulosin, prazosin | α1-adrenoceptor antagonist (67) | Decreased in male fertility, mating uninhibited and reversible libido (67) | It causes an increase in preimplantation losses and a significant decrease in ejaculatory competence (67) |
| 16. | Serotonin-norepinephrine reuptake | Control sperm transit time (68) | Sibutramine | Non-selective serotonin-norepinephrine reuptake inhibitor (68) | Reduced sperm quality (68) | |
| 17. | Glyceraldehyde 3-phosphate dehydrogenase, spermatogenic (GAPDHS) | Spermatogenesis (69) | (S)-α-chlorohydrin (SACH) | GAPDHS inhibitor | Disturbed spermatogenesis through blocking the cAMP/PKA pathway in sperm (69) | |
| 18. | Adenylyl cyclase-10 (ADCY10) | The primary enzyme responsible for the production of cAMP in sperm (70) | CE (2HE) KH7 DIDS ASI-8 Bithionol LRE1 | S-Allylcysteine (sAC) inhibitors | Decreased male fertility through reduced sperm motility and capacitation (70) | The correlation between dominant absorptive hypercalciuria and ADCY10 has not slowed the development and optimization of ADCY inhibitors as nonhormonal contraceptives (70) |
| WIN18.446: N,N'-1,8-Octanediylbis (2,2-dichloroacetamide), BMS-189453: (4-[(1E)-2-(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethenyl]-benzoic acid, JQ1: ((S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f,1,2,4]triazolo[4,3-a,1,4]diazepin-6-yl)acetate), RU1968: ((1R,3aR,3bR,9bR,11aR)-1-[(1R)-1- [2-(dimethylamino)ethyl]amino ethyl]-11a-methyl-1H,2H,3H,3aH,3bH,4H,5H,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-7-ol) | ||||||