Sertraline

Biological target Sertraline is an aryl-substituted tetrahydronaphthalene derivative which selectively inhibits the plasma membrane serotonin transporter (SERT) and thereby blocks serotonin re-uptake from the neuronal synapse. 

Therapeutic profile As a selective serotonin reuptake inhibitor (SSRI), sertraline is a widely used drug for the treatment of depression and anxiety-related disorders. 

Synthetic highlights A variety of pathways have been taken in the synthetic approach to sertraline. These include stereoselective reduction of ketones and imines under kinetic and thermodynamic control, using diastereoselective or enan-tioselective catalysts and reagents, desymmetrization of oxabenzonorbomadiene followed by the Suzuki coupling of arylboronic acids and vinyl halides and Pd-Catayzed (Tsuji-Trost) coupling of arylboronic acids and allylic esters. For the production of sertraline, the simulated moving bed (SMB), a cost-effective technology, has been introduced. 

Sertraline hydrochloride [1, (lS, 4S )-l-methylamino-4-(3 4 -dichlorophenyl)-tetra-hydronaphthalene, Zo/o/t )] is an inhibitor of serotonin re-uptake, and an important pharmaceutical agent for the treatment of depression as well as dependency- and other anxiety-related disorders [1,2], 

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SSRIs are widely used for treatment of depression, as well as, for example, panic disorders and obsessive—compulsive disorder. These dmgs are well recognized as clinically effective antidepressants having an improved side-effect profile as compared to the TCAs and irreversible MAO inhibitors. Indeed, these dmgs lack the anticholinergic, cardiovascular, and sedative effects characteristic of TCAs. Their main adverse effects include nervousness /anxiety, nausea, diarrhea or constipation, insomnia, tremor, dizziness, headache, and sexual dysfunction. The most commonly prescribed SSRIs for depression are fluoxetine (31), fluvoxamine (32), sertraline (52), citalopram (53), and paroxetine (54). SSRIs together represent about one-fifth of total worldwide antidepressant unit sales. 

This was converted to its imine with methylamine catalyzed by titanium tetrachloride and then sodium borohydride reduction produced 17 as a mixture of diastereomers. This was resolved by column chromatography to give sertraline [5]. Dextrorotatory cis sertraline is substantially more potent than its isomers. 

Selective serotonine reuptake inhibitor (SSRI) is an abbreviation for the class of antidepressants known as the Selective Serotonin Reuptake Inhibitors. Examples of SSRIs include fluoxetine, paroxetine, citalopram, and sertraline. These drugs selectively inhibit the serotonin transporter thus prolonging the synaptic lifespan of the neurotransmitter serotonin. 

Use of die MAOIs must be discontinued 2 weeks before the administration of die SSRIs. When the SSRIs are administered witii die tricyclic antidepressants, tiiere is an increased risk of toxic effects and an increased tiierapeutic effect. When sertraline is administered witii a MAOI, a potentially fatal reaction can occur. Sjymptoms of a serious reaction include hyper-tiiermia, rigidity, autonomic instability witii fluctuating vital signs and agitation, delirium, and coma Sertraline blood levels are increased when administered witii cimetidine. 

Few methodologies have either the diversity of synthetic transformations or the high level of product selectivity as catalytic reactions with the intermediate involvement of metal carbenes [ 1-5]. They provide synthetic opportunities that are clearly demonstrated in the preparation of the antidepressant sertraline (1)... 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

This methodology has provided an alternative, highly enantioselective route to sertraline 1 [94]. Insertion into the oxygen-activated CH2 position of allyl ethers yields syn-aldol products with high stereocontrol (Eq. 13) [97], and... 

C, .H,2Cl20 79560-19-3) see Sertraline [l-(3,4-dichlorophenyl)ethyl]hydrazine (CjHioCLNj 55294-31-0) see Muzolimine l-(2,4-dichlorophenyl)-2-(lFf-imidazol-l-yl)ethanol... 

Ci2H Cl2N03 4402-83-9) see Dicloxacillin [(2,6-dichlorophenyl)phenylamino]oxoacetyl chloride (C14H8CI7NO2 24542-55-0) see Diclofenac ( )-4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (C(,Hi4Cl202 79560-18-2) see Sertraline... 

Pettinati HM, Volpicelli JR, Kranzler HR, et al Sertraline treatment for alcohol dependence interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 24 1041-1049, 2000... 

Antidepressants Desipramine, imipramine, sertraline, fluoxetine, paroxetine, venlafaxine, bupropion, nefazodone, mirtazapine, gepirone, amineptine Mixed findings suggest that better designed studies may find a niche for some of these drugs. Amineptine was effective for withdrawal symptoms. 

Decision analytic models have been constmcted to compare the costs of TCAs with those of SSRIs and other compounds. These comparisons have included imipramine or amitriptyline versus paroxetine or sertraline (Stewart, 1994) imipramine versus paroxetine Qonsson and Bebbington, 1994 McFarland, 1994 Lapierre et al, 1995) fluoxetine versus amitriptyline, clomipramine, doxepin and imipramine (Le Pen et al, 1994) venlafaxine versus amitriptyline, desipramine. 

The only study conducted in the UK (Forder et al, 1996) employed a retrospective, quasi-experimental design in which patients from an open-label study of sertraline were compared with age- and gender-matched patients prescribed TCAs in a primary care setting. The study found that sertraline was more effective than TCAs (87% versus 74%,... 

Differences exist in primary care between the patterns of prescribing fluoxetine, paroxetine or sertraline, which may influence cost outcomes. Sertraline-treated patients are more likely to have their dose increased (Sclar et al, 1995 Donoghue, 1998), and to drop out of treatment prematurely (Donoghue, 1998). The apparent need to titrate doses upwards with sertraline may require more involvement by the clinician and may delay response to treatment, with resultant increases in direct health costs (Sclar et al, 1995). However, these economic findings are retrospective, may suffer from selection bias, and being derived from HMO patients may not be generalizable to other populations confirmation in further studies is required. 

Forder J, Kavanagh S, Fenyo A (1996). A comparison of the cost-effectiveness of sertraline versus tricyclic antidepressants in primary C2src. J Affective Disord 58y 97—111. 

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