Abstract
A novel stereoselective synthesis of (S)-dapoxetine starting from commercially available transcinnamyl alcohol is described. Sharpless Asymmetric Epoxidation (SAE) is utilized as the key step in this synthetic strategy.
Highlights
It has been suggested that premature ejaculation (PE) might be associated with perturbations in serotonergic 5-hydroxytryptamine (5-HT) neurotransmission.[1,2] It has been proposed that PE may be caused by decreased central serotonergic signaling, hyposensitivity of the 5-HT2C receptor, or hypersensitivity of the 5-HT1A receptor, all of which have been shown to decrease ejaculatory latency time in animal model systems.[3,4] PE is a common problem, which may be associated with considerable anxiety, frustration, and negative impact on affected men and their sexual partners
The off-label use of antidepressant selective serotonin reuptake inhibitor (SSRI) such as fluoxetine, sertraline, and paroxetine may increase ejaculatory latency time[11,12,13] these SSRIs do not reach peak plasma concentrations for several hours after administration; many require a long lead-in dosing period for efficacy[1] and the typically long half-lives of these drugs can result in significant drug accumulation in the body, increased exposure to medication and, an increased likelihood of adverse events.[6,14]
The Sharpless asymmetric epoxidation (SAE) can be envisioned as a powerful tool offering considerable opportunities for synthetic manipulations,[19] which has been employed as a key step in our synthetic strategy as shown in Scheme 1
Summary
It has been suggested that premature ejaculation (PE) might be associated with perturbations in serotonergic 5-hydroxytryptamine (5-HT) neurotransmission.[1,2] It has been proposed that PE may be caused by decreased central serotonergic signaling, hyposensitivity of the 5-HT2C receptor, or hypersensitivity of the 5-HT1A receptor, all of which have been shown to decrease ejaculatory latency time in animal model systems.[3,4] PE is a common problem, which may be associated with considerable anxiety, frustration, and negative impact on affected men and their sexual partners. The American Urological Association as well as the International Consultation on Sexual Dysfunctions recommends the off-label use of SSRIs, which increase 5-HT neurotransmission, for the management of PE.[1,9,10] the off-label use of antidepressant SSRIs such as fluoxetine, sertraline, and paroxetine may increase ejaculatory latency time[11,12,13] these SSRIs do not reach peak plasma concentrations for several hours after administration; many require a long lead-in dosing period for efficacy[1] and the typically long half-lives of these drugs can result in significant drug accumulation in the body, increased exposure to medication and, an increased likelihood of adverse events.[6,14] In addition, men taking antidepressant SSRIs daily have reported sexual side effects such as decreased libido and erectile dysfunction after prolonged treatment with these drugs.[6] If approved by the Food and Drug Administration (FDA), this would make dapoxetine join the ranks of erectile dysfunction drugs such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra) and some dopamine agonists such as cabergoline (Dostinex) and pramipexole, as drugs which can be used to improve male sexual health.[15]
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