Sertraline

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https://en.wikipedia.org/wiki/Sertraline

 

"Lustral" redirects here. For other uses, see Lustral (disambiguation).

 

Sertraline

Clinical data
Pronunciation	/ˈsərtrəˌliːn/
Trade names	Zoloft and others
AHFS/Drugs.com	Monograph
MedlinePlus	a697048
Pregnancy category	AU: C US: C (Risk not ruled out)
Addiction liability	None
Routes of administration	By mouth (tablets and solution)
Drug class	Selective serotonin reuptake inhibitor
ATC code	N06AB06 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	44%
Protein binding	98.5%
Metabolism	Hepatic (N-demethylation mainly by CYP2B6)
Metabolites	norsertraline
Elimination half-life	~23–26 h (66 h [less-active metabolite, norsertraline])
Excretion	Renal
Identifiers
CAS Number	79617-96-2
PubChem CID	68617
IUPHAR/BPS	4798
DrugBank	DB01104
ChemSpider	61881
UNII	QUC7NX6WMB
KEGG	D02360
ChEBI	CHEBI:9123
ChEMBL	ChEMBL809
CompTox Dashboard (EPA)	DTXSID6023577
Chemical and physical data
Formula	C17H17Cl2N
Molar mass	306.229 g/mol g·mol−1
3D model (JSmol)	Interactive image

Sertraline, sold under the trade name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive–compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder. Sertraline is taken by mouth.

Common side effects include diarrhea, sexual dysfunction, and troubles with sleep. Serious side effects include an increased risk of suicide in those less than 25 years old and serotonin syndrome. It is unclear whether use during pregnancy or breastfeeding is safe. It should not be used together with MAO inhibitor medication. Sertraline is believed to work by increasing serotonin effects in the brain.

Sertraline was approved for medical use in the United States in 1991 and initially sold by Pfizer. It is currently available as a generic medication. In the United States, the wholesale cost is about US$1.50 per month as of 2018. In 2016, it was the most prescribed psychiatric medication in the United States, with over 37 million prescriptions.

Medical uses

Sertraline is used for a number of conditions, including major depressive disorder (MDD), obsessive–compulsive disorder (OCD), body dysmorphic disorder (BDD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). It has also been used for premature ejaculation and vascular headaches but evidence of the effectiveness in treating those conditions is not robust. Sertraline is not approved for use in children except for those with OCD.

Depression

It is unclear if sertraline is any different from another SSRI, paroxetine, for depression; though escitalopram may have some benefits over sertraline.

Evidence does not show a benefit in children with depression.

With depression in dementia, there is no benefit compared to either placebo or mirtazapine.

Comparison with other antidepressants

Tricyclic antidepressants (TCAs) as a group are considered to work better than SSRIs for melancholic depression and in inpatients, but not necessarily for simply more severe depression. In line with this generalization, sertraline was no better than placebo in inpatients and as effective as the TCA clomipramine for severe depression. The comparative efficacy of sertraline and TCAs for melancholic depression has not been studied. A 1998 review suggested that, due to its pharmacology, sertraline may be more efficacious than other SSRIs and equal to TCAs for the treatment of melancholic depression.

A meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with unipolar MDD. Reboxetine was significantly worse.

Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, and mirtazapine. There is low quality evidence that sertraline is more efficacious for the treatment of depression than fluoxetine.

Elderly

Sertraline used for the treatment of depression in elderly (older than 60) patients was superior to placebo and comparable to another SSRI fluoxetine, and TCAs amitriptyline, nortriptyline (Pamelor) and imipramine. Sertraline had much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurred more frequently with sertraline. In addition, sertraline appeared to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup. A 2003 trial of sertraline vs. placebo in elderly patients showed a statistically significant (that is, unlikely to occur by chance), but clinically very modest improvement in depression and no improvement in quality of life.

A meta-analysis on SSRIs and SNRIs that look at partial response (defined as at least a 50% reduction in depression score from baseline) found that sertraline, paroxetine and duloxetine were better than placebo.

Obsessive–compulsive disorder

Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on intention to treat analysis, performed better than the gold standard of OCD treatment clomipramine. It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression. The onset of action is also slower for OCD than for depression.

Cognitive behavioral therapy alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.

Panic disorder

Treatment of panic disorder with sertraline results in a decrease of the number of panic attacks and an improved quality of life. In four double-blind studies sertraline was shown to be superior to placebo for the treatment of panic disorder. The response rate was independent of the dose. In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as "improved" on sertraline reported better quality of life than the ones who "improved" on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo. Sertraline was equally effective for men and women. While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, fluvoxamine and paroxetine) indicates approximate equivalence of these medications.

Other anxiety disorders

Sertraline is effective for the treatment of social phobia. Improvement in scores on the Liebowitz Social Anxiety Scale were found with sertraline but not with placebo. In children, a combination of sertraline and cognitive behavioural therapy had a superior response rate to each intervention alone, and both sertraline and CBT were alone superior to placebo and not significantly different from one another.

There is tentative evidence that sertraline, as well as other SSRI/SNRI antidepressants, can help with the symptoms of general anxiety disorder. The trials have generally been short in length (6–12 weeks) and pharmacological treatments are associated with more frequent side effects.

Premenstrual dysphoric disorder

SSRIs, including sertraline, reduce the symptoms of premenstrual syndrome. Side effects such as nausea are common. Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome. Significant improvement was observed in 50–60% of cases treated with sertraline vs. 20–30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline. Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment.

Other indications

Sertraline when taken daily can be useful for the treatment of some aspects of premature ejaculation. A disadvantage of SSRIs is that they require continuous daily treatment to delay ejaculation significantly, and it is not clear how they affect psychological distress of those with the condition or the person's control over ejaculation timing.

The benefit of sertraline in PTSD is not significant per the National Institute of Clinical Excellence. Others, however, do feel that there is a benefit from its use.

Side effects

Zoloft 50 mg & 25 mg tablets (US)

 

Zoloft 100 mg tablets (AU)

Compared to other SSRIs, sertraline tends to be associated with a higher rate of psychiatric side effects and diarrhea. It tends to be more activating (that is, associated with a higher rate of anxiety, agitation, insomnia, etc.) than other SSRIs, aside from fluoxetine.

Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). Although the difference did not reach statistical significance, the weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% gained a large amount of weight (defined as more than 7% gain). This result compares favorably with placebo, where, according to the literature, 3–6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group. The incidence of diarrhea is higher with sertraline—especially when prescribed at higher doses—in comparison to other SSRIs.

Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination.^[58][59] In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls.^[60] In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these effects on cognition and vigilance. Sertraline's effect on the dopaminergic system may explain the risk of oromandibular dystonia.

Sexual

Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder and difficulty achieving orgasm. The frequency of sexual side effects depends on whether they are reported by people spontaneously, as in the manufacturer's trials, or actively solicited by physicians. While nefazodone, bupropion, and reboxetine do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment. Sexual arousal disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes counteracted these side effects, so that sexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved.

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in these cases include genital anesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates of PSSD are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including sertraline) is associated with shorter average duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0 .4="" among="" an="" children="" defects="" early="" heart="" in="" increased="" is="" it="" mothers="" of="" p="" points="" pregnancy.="" prescribed="" rate="" septal="" ssri="" there="" uncertain="" were="" whether="" whose="">

Suicide

The FDA requires all antidepressants, including sertraline, to carry a boxed warning stating that antidepressants may increase the risk of suicide in persons younger than 25 years. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal ideation and behavior in children and adolescents, and a 50% increase of suicidal behavior in the 18–24 age group.

Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behavior with a marginal statistical significance by 37% or 50% depending on the statistical technique used. The authors of the FDA analysis note that "given the large number of comparisons made in this review, chance is a very plausible explanation for this difference". The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior. Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.

Concerns have been raised that suicidal acts among participants in multiple studies were not reported in published articles reporting the studies.

Discontinuation syndrome

Antidepressant discontinuation syndrome is a condition that can occur following the interruption, dose reduction, or discontinuation of antidepressant drugs, including sertraline. The symptoms can include flu-like symptoms, "brain zaps," and disturbances in sleep, senses, movement, mood, and thinking. In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering off rate.

Overdose

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. As with most other SSRIs its toxicity in overdose is considered relatively low.

Interactions

Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol. This effect is dose-dependent. In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6. Sertraline is often used in combination with stimulant medication for the treatment of co-morbid depression and/or anxiety in ADHD. Amphetamine metabolism inhibits enzyme CYP2D6, but has not been known to interfere with Sertraline metabolism.

Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; this effect was not considered to be clinically relevant.^[7] As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.

Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolized in the liver. Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.

Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.

According to the label, sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide (Orap). Sertraline concentrate contains alcohol, and is therefore contraindicated with disulfiram (Antabuse). The prescribing information recommends that treatment of the elderly and patients with liver impairment "must be approached with caution." Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.

Pharmacology

Sertraline is a selective serotonin re-uptake inhibitor. It targets the sodium dependent serotonin transporter to inhibit the re-uptake of serotonin by neurons. This increases the concentration of serotonin in the synaptic cleft, meaning more is available to act on the post synaptic neurons resulting in antidepressant effects. Sertraline does not inhibit noradrenalin re-uptake, has little anticholinergic activity and has less sedative and cardiovascular effects than tricyclic antidepressant drugs.

Mechanism of action

Sertraline

Site	Ki (nM)	Species
SERT	0.4 2.8 (IC50)	Human
NET	420–817 925 (IC50)	Human
DAT	22–25 315 (IC50)	Human
5-HT1A	>35,000	Human
5-HT2A	2,207	Rat
5-HT2C	2,298	Pig
α1	36–480	Human
α2	477–4,100	Human
D2	10,700	Human
H1	24,000	Human
mACh	427–2,100	Human
σ1	32–57	Rat
σ2	5,297	Rat
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to or inhibits the site.

Sertraline acts as a potent serotonin reuptake inhibitor (SRI), with an affinity (K_i) for the serotonin transporter (SERT) of 0.4 nM and an IC₅₀ value of 2.8 nM, according to a couple of studies. It is highly selective in its inhibition of serotonin reuptake. By inhibiting the reuptake of serotonin, sertraline increases extracellular levels of serotonin and thereby increases serotonergic neurotransmission in the brain. It is this action that is thought to be responsible for the antidepressant, anxiolytic, and antiobsessional effects of sertraline.

Sertraline does not have significant affinity for the norepinephrine transporter (NET) or the serotonin, dopamine, adrenergic, histamine, or acetylcholine receptors. On the other hand, it does show high affinity for the dopamine transporter (DAT) and the sigma σ₁ receptor (but not the σ₂ receptor). However, its affinities for these sites are around 100-fold or lower than for the SERT.

Dopamine reuptake inhibition

Sertraline is an SSRI, but, uniquely among most antidepressants, it shows relatively high (nanomolar) affinity for the DAT in addition to the SERT. As such, it has been suggested that clinically it may weakly inhibit the reuptake of dopamine, particularly at high dosages. For this reason, sertraline has sometimes been described as a serotonin–dopamine reuptake inhibitor (SDRI). This is relevant as dopamine is thought to be involved in the pathophysiology of depression, and increased dopaminergic neurotransmission by sertraline in addition to serotonin may have additional benefits against depression.

Tatsumi et al. (1997) found K_i values of sertraline at the human SERT, DAT, and NET of 0.29, 25, and 420 nM, respectively. The selectivity of sertraline for the SERT over the DAT was 86-fold. In any case, of the wide assortment of antidepressants assessed in the study, sertraline showed the highest affinity of them all for the DAT, even higher than the norepinephrine–dopamine reuptake inhibitors (NDRIs) nomifensine (K_i = 56 nM) and bupropion (K_i = 520 nM). Sertraline also has similar affinity for the DAT as the NDRI methylphenidate (K_i = 24 nM). Tametraline (CP-24,441), a very close analogue of sertraline and the compound from which sertraline was originally derived, is an NDRI that was never marketed.

Single doses of 50 to 200 mg sertraline have been found to result in peak plasma concentrations of 20 to 55 ng/mL (65–180 nM), while chronic treatment with 200 mg/day sertraline, the maximum recommended dosage, has been found to result in maximal plasma levels of 118 to 166 ng/mL (385–542 nM). However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%. Hence, only 1.5% is free and theoretically bioactive. Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one-third of the K_i value that Tatsumi et al. found with sertraline at the DAT. A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM).^[7] This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the K_i of sertraline for the DAT.

As such, it seems unlikely that sertraline would produce much inhibition of dopamine reuptake even at clinically used dosages well in excess of the recommended maximum clinical dosage. This is in accordance with its 86-fold selectivity for the SERT over the DAT according to Tatsumi et al. and hence the fact that nearly 100-fold higher levels of sertraline would be necessary to also inhibit dopamine reuptake. In accordance, while sertraline has very low abuse potential and may even be aversive at clinical dosages, a case report of sertraline abuse described dopaminergic-like effects such as euphoria, mental overactivity, and hallucinations only at a dosage 56 times the normal maximum and 224 times the normal minimum. For these reasons, significant inhibition of dopamine reuptake by sertraline at clinical dosages is controversial, and occupation by sertraline of the DAT is thought by many experts to not be clinically relevant.

Sigma receptor antagonism

Sertraline has relatively high (nanomolar) affinity for the sigma σ₁ receptor. Conversely, it has low (micromolar) and insignificant affinity for the σ₂ receptor. It acts as an antagonist of the σ₁ receptor, and is able to reverse σ₁ receptor-dependent actions of fluvoxamine, a potent agonist of the receptor, in vitro. However, the affinity of sertraline for the σ₁ receptor is more than 100-fold lower than for the SERT. Although there could be a role for the σ₁ receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear and perhaps questionable.

Sertraline is associated with a significantly higher incidence of diarrhea than other SSRIs, especially at higher doses. Agonists of the σ₁ receptor such as igmesine have been found to inhibit intestinal secretion and bacteria-induced secretory diarrhea in animal studies, and igmesine showed preliminary evidence of efficacy for the treatment of diarrhea in a small clinical trial. Sertraline is the only SSRI that acts as an antagonist of the σ₁ receptor, so this action could in theory be responsible for its higher relative incidence of diarrhea. 

Neurosteroidogenesis enhancement

Sertraline has been found to directly act on the enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD) and modulate its activity, thereby enhancing the conversion of 5α-dihydroprogesterone into the neurosteroid allopregnanolone and thus increasing the production of allopregnanolone in the brain. The same is true for certain other SSRIs including fluoxetine and paroxetine. However, a subsequent study failed to reproduce these findings, and a direct interaction of SSRIs with 3α-HSD is controversial. In any case, another study found that, at least in the case of fluoxetine and its active metabolite norfluoxetine, these drugs normalized low allopregnanolone levels in socially isolated mice and at low doses that were inactive on serotonin reuptake (10- to 50-fold lower, specifically). On the basis of these results, SSRIs like fluoxetine and norfluoxetine were described as selective brain steroidogenic stimulants (SBSSs).

Pharmacokinetics

Norsertraline (desmethylsertraline)—sertraline's chief active metabolite

 

Sertraline is absorbed slowly when taken orally, achieving its maximal concentration in the plasma 4 to 6 hours after ingestion. In the blood, it is 98.5% bound to plasma proteins and a half life of 25 to 26 hours. Sertraline is metabolised in the liver by demethylation to an inactive metabolite. According to in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms: CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4. It appeared unlikely that inhibition of any single isoform could cause clinically significant changes in sertraline pharmacokinetics. No differences in sertraline pharmacokinetics were observed between people with high and low activity of CYP2D6; however, poor CYP2C19 metabolizers had a 1.5-times-higher level of sertraline than normal metabolizers. In vitro data also indicate that the inhibition of CYP2B6 should have even greater effect than the inhibition of CYP2C19, while the contribution of CYP2C9 and CYP3A4 to the metabolism of sertraline would be minor. These conclusions have not been verified in human studies. Sertraline can be deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo. The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.

Non-amine metabolites may also contribute to the antidepressant effects of this medication. Sertraline deaminated is O-2098, a compound that has been found to inhibit the dopamine reuptake transporter proteins in spite of its lack of a nitrogen atom.

Its chief active metabolite is norsertraline (N-desmethylsertraline) which is significantly less biologically active than its parent compound.

Metabolism of sertraline in human liver microsomes.

 

History

Skeletal formulae of chlorprothixene and tametraline, from which sertraline was derived

 

The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds based on the structure of the neuroleptic chlorprothixene. Further work on these compounds led to lometraline and then to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type—in that sense their inquiry was not "very goal driven", and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even "did not have a formal project team". The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.

Sertraline was approved by the U.S. Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of MDD.

Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data). It was measured as among the top ten drugs ranked by cost to the Australian government in 1998 and 2000–01, having cost $45 million and $87 million in subsidies respectively. Sertraline is less popular in the UK (2003 data) and Canada (2006 data)—in both countries it was fifth (among drugs marketed for the treatment of MDD, or antidepressants), based on the number of prescriptions.

Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe OCD. In 2003, the U.K. Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a boxed warning concerning pediatric suicidal behavior to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24.

Society and culture

Generic availability

The U.S. patent for Zoloft expired in 2006, and sertraline is now available in generic form and is marketed under many brand names worldwide.

Stereochemistry of ketonization of enols and enolates

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Stereochemistry_of_ketonization_of_enols_and_enolates 

 

In the stereochemistry of ketonization of enols and enolates, theory is provided explaining the diastereoselectivity observed in the conversion of certain enols and enolates into the corresponding ketone.

 

 

Introduction

Ketones and their corresponding enols are isomers, termed tautomers. These are easily interconvertible. But simple enols are not generally stable and of considerably higher energy than the corresponding ketones. Nevertheless, a very large number of organic reactions proceed via enolic intermediates. Thus the behavior of enols is critical to an understanding of myriad organic reactions.

Many of these enols, formed in an organic reaction, a priori, can lead onward and afford two diastereomers on ketonization. If one knows the stereochemistry of ketonization of these enolic intermediates, then one can predict the stereochemistry of myriad organic reactions.

It was proposed in 1955 that the kinetic protonation of enolic species proceeds with an early transition state with the alpha carbon being close to sp2 hybridized. The proton donor selectively approaches the less hindered face of the enolate, thus leading to the less stable of two diastereomers. Reactions controlled in this fashion include:

• (a) decarboxylation of malonic acids
• (b) decarboxylation of beta-keto acids
• (c) the Michael addition of nucleophiles to unsaturated carbonyl compounds
• (d) the Birch reduction of enones
• (e) the deprotonation – protonation of carbonyl compounds
• (f) the dehalogenation of alpha-haloketones
• (f) the Norrish Type II Reaction
• and many more.

Kinetic or thermodynamic control

Protonation from the less hindered face of an enol leads to the less stable of two, a priori, diastereomers. In this example there are two different reactions which afford the enol as a transient intermediate. One is the treatment of an α-bromoketone with dilute HI in acetone. The second is the reaction of an enol acetate with methyllithium. The first of the two reactions is an example of microscopic reversibility. This is the reverse of bromination of a ketone, a reaction well-known to proceed via the enol as an intermediate. This is an example with extreme stereoselectivity due to the severe steric hindrance of an ethano-bridge.

With an acid catalyst as well as with a base catalyst such as sodium ethoxide a thermodynamic equilibrium is achieved. The diastereomer formed now has the acetyl group equatorial. 

Figure 2. Equilibration of the Diastereomers via the Common Enol.

Unusual case of a phenyl pyridyl enol

Figure 3 show the ketonization results for the two Phenyl-Pyridyl diastereomers. In the exo-pyridyl isomer on the left, the usual steric hindrance control blocks protonation from above. That is, the phenyl group is positioned directly above the enolic alpha carbon and protonation must occur from below. In contrast, in the case of the endo pyridyl isomer on the right, the basic pyridyl moiety proves capable of picking up the proton first and then delivering it to the alpha-carbon from this upper, hindered side. Results from intramolecular proton delivery is the reverse of the common stereochemistry.

Figure 3. Two Phenyl-Pyridyl Enol Diastereomers. 

A Typical example; an enol generated from an alpha-bromoketone

Figure 4. The Example of Ketonization of the Enol of 4-Phenyl-1-Benzoylcyclohexane.

In this example the enol intermediate is generated from either the cis- or the trans-stereoisomer of 1-bromo-1-benzoyl-4-phenylcyclohexane using zinc as the reagent. The endo proton approach is blocked by two axial hydrogens. This example is somewhat more typical than those shown earlier since the stereoselectivity is only in the range of 60 to 70 percent favoring formation of the (less stable) cis product.

Enantiomer

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Enantiomer

 

(S)-(+)-lactic acid (left) and (R)-(–)-lactic acid (right) are nonsuperposable mirror images of each other

 

In chemistry, an enantiomer (/ɪˈnæntiəmər, ɛ-, -tioʊ-/ ə-NAN-tee-ə-mər; from Greek ἐνάντιος (enántios), meaning 'opposite', and μέρος (méros), meaning 'part') (archaically termed optical isomer, antipode, or optical antipode) is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right hands are mirror images of each other that cannot appear identical simply by reorientation. A single chiral atom or similar structural feature in a compound causes that compound to have two possible structures which are non-superposable, each a mirror image of the other. Each member of the pair is termed an enantiomorph (enantio = opposite; morph = form); the structural property is termed enantiomerism. The presence of multiple chiral features in a given compound increases the number of geometric forms possible, though there may still be some perfect-mirror-image pairs.

A sample of a chemical is considered enantiopure (also termed enantiomerically pure) when it has, within the limits of detection, molecules of only one chirality.

When present in a symmetric environment, enantiomers have identical chemical and physical properties except for their ability to rotate plane-polarized light (+/−) by equal amounts but in opposite directions (although the polarized light can be considered an asymmetric medium). Such compounds are therefore described as optically active, with specific terms for each enantiomer based on the direction: a dextrorotatory compound rotates light a clockwise (+) direction whereas a levorotatory compound rotates light in a counter-clockwise (–) direction. A mixture of equal number of both enantiomers is called a racemic mixture or a racemate. In a racemic mixture, the amount of positive rotation is exactly counteracted by the equal amount of negative rotation, so the net rotation is zero (the mixture is not optically active). For all intents and purposes, pairs of enantiomers have the same Gibbs free energy. However, theoretical physics predicts that due to parity violation of the weak nuclear force (the only force in nature that can "tell left from right"), there is actually a minute difference in energy between enantiomers (on the order of 10⁻¹² eV or 10⁻¹⁰ kJ/mol or less) due to the weak neutral current mechanism. This difference in energy is far smaller than energy changes caused by even a trivial change in molecular conformation and far too small to measure by current technology, and is therefore chemically inconsequential.

Enantiomer members often have different chemical reactions with other enantiomer substances. Since many biological molecules are enantiomers, there is sometimes a marked difference in the effects of two enantiomers on biological organisms. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiological effects, while the other enantiomer is less active, inactive, or sometimes even productive of adverse effects. Owing to this discovery, drugs composed of only one enantiomer ("enantiopure") can be developed to make the drug work better and sometimes eliminate some side effects. An example is eszopiclone (Lunesta), which is just a single enantiomer of an older racemic drug called zopiclone. One enantiomer is responsible for all the desired effects, while the other enantiomer seems to be inactive, and the so the dose of eszopiclone is half that of zopiclone.

In chemical synthesis of enantiomeric substances, non-enantiomeric precursors inevitably produce racemic mixtures. In the absence of an effective enantiomeric environment (precursor, chiral catalyst, or kinetic resolution), separation of a racemic mixture into its enantiomeric components is impossible, although certain racemic mixtures spontaneously crystallize in the form of a racemic conglomerate, in which crystals of the enantiomers are physically segregated and may be separated mechanically (e.g., the enantiomers of tartaric acid, whose crystallized enantiomers were separated with tweezers by Pasteur). However, most racemates will crystallize in crystals containing both enantiomers in a 1:1 ratio, arranged in a regular lattice.

Naming conventions

The R/S system is an important nomenclature system used to denote distinct enantiomers. Another system is based on prefix notation for optical activity: (+)- and (−)- or d- and l-. The Latin words for left are laevus and sinister, and the word for right is dexter (or rectus in the sense of correct or virtuous). The English word right is a cognate of rectus. This is the origin of the L/D and S/R notations, and the employment of prefixes levo- and dextro- in common names.

Criterion of enantiomerism

Fischer projection of meso-tartaric acid

 

An asymmetric carbon atom is one which has bonds with four different atoms or groups, so that these bonds can be arranged in two different ways which are not superposable. Most compounds that contain one or more asymmetric carbon (or other element with a tetrahedral geometry) atoms show enantiomerism, but this is not always true. Compounds that contain two or more asymmetric carbon atoms but have a plane of symmetry with respect to the whole molecule are known as meso compounds. A meso compound does not have a mirror image stereoisomer because it is its own mirror image (i.e., it and its mirror image are the same molecule). For instance, meso tartaric acid (shown on the right) has two asymmetric carbon atoms, but it does not exhibit enantiomerism because each of the two halves of the molecule is equal and opposite to the other and thus is superposable on its geometric mirror image. Conversely, there exist forms of chirality that do not require individual asymmetric atoms. In fact, there are four distinct types of chirality: central, axial, planar, and helical chirality. Having an enantiomer by virtue of an asymmetric carbon atom represents the most common type of central chirality. The other three types of chirality do not involve asymmetric carbon atoms, and even central chirality does not require the center of chirality to be located at a carbon or any other atom. Consequently, while the presence of an asymmetric carbon atom is a convenient characteristic to look for when determining whether a molecule will have an enantiomer, it is neither sufficient nor necessary as a criterion.

As a rigorous criterion, a molecule is chiral, and will therefore possess an enantiomer, if and only if it belongs to one of the chiral point groups: C_n, D_n, T, O, and I. However, as a caveat, enantiomers are not necessarily isolable if there is an accessible pathway for racemization at a given temperature and timescale. For example, amines with three distinct substituents are chiral, but with the exception of only a few atypical cases (e.g. substituted N-chloroaziridines), they rapidly planarize and invert ("umbrella inversion") at room temperature, leading to racemization. If the racemization is fast enough, the molecule can often be treated as an achiral, averaged structure. 

Examples

Structures of the two enantiomeric forms (S left, R right) of mecoprop

 

Enantiomers of citalopram. The top is (R)-citalopram and the bottom is (S)-citalopram.

 

An example of such an enantiomer is the sedative thalidomide, which was sold in a number of countries around the world from 1957 until 1961. It was withdrawn from the market when it was found to cause birth defects. One enantiomer caused the desirable sedative effects, while the other, unavoidably present in equal quantities, caused birth defects.

The herbicide mecoprop is a racemic mixture, with the (R)-(+)-enantiomer ("Mecoprop-P", "Duplosan KV") possessing the herbicidal activity.

Another example is the antidepressant drugs escitalopram and citalopram. Citalopram is a racemate [1:1 mixture of (S)-citalopram and (R)-citalopram]; escitalopram [(S)-citalopram] is a pure enantiomer. The dosages for escitalopram are typically 1/2 of those for citalopram. 

Enantioselective preparations

There are two main strategies for the preparation of enantiopure compounds. The first is known as chiral resolution. This method involves preparing the compound in racemic form, and separating it into its isomers. In his pioneering work, Louis Pasteur was able to isolate the isomers of tartaric acid because they crystallize from solution as crystals each with a different symmetry. A less common method is by enantiomer self-disproportionation. 

The second strategy is asymmetric synthesis: the use of various techniques to prepare the desired compound in high enantiomeric excess. Techniques encompassed include the use of chiral starting materials (chiral pool synthesis), the use of chiral auxiliaries and chiral catalysts, and the application of asymmetric induction. The use of enzymes (biocatalysis) may also produce the desired compound.

Enantioconvergent synthesis is the synthesis of one enantiomer from a racemic precursor molecule utilizing both enantiomers. Thus, the two enantiomers of the reactant produce a single enantiomer of product.

Enantiopure medications

Advances in industrial chemical processes have made it economic for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers. In some cases, the enantiomers have genuinely different effects. In other cases, there may be no clinical benefit to the patient. In some jurisdictions, single-enantiomer drugs are separately patentable from the racemic mixture. It is possible that only one of the enantiomers is active. Or, it may be that both are active, in which case separating the mixture has no objective benefits, but extends the drug's patentability.

Quasi-enantiomers

Quasi-enantiomers are molecular species that are not strictly enantiomers, but behave as if they are. Quasi-enantiomers have applications in parallel kinetic resolution.