Lurasidone

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Lurasidone
Lurasidone structure.svg
Lurasidone3Dan.gif
Systematic (IUPAC) name
(3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl]methyl}cyclohexyl)methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione
Clinical data
Trade namesLatuda
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa611016
Licence dataUS Daily Med:link
Pregnancy cat.B1 (AU) B (US)
Legal statusPrescription Only (S4) (AU) -only (CA) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability9–19% (oral)[1]
MetabolismHepatic (CYP3A4-mediated)[1]
Half-life18 hours[1]
ExcretionFaecal (~80%), renal (~9%)[1]
Identifiers
CAS number367514-87-2
ATC codeN05AE05
PubChemCID 213046
ChemSpider184739
UNII22IC88528T YesY
ChEBICHEBI:70735 YesY
ChEMBLCHEMBL1237021
SynonymsSM-13,496
Chemical data
FormulaC28H36N4O2S 
Mol. mass492.676 g/mol
 
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Lurasidone
Lurasidone structure.svg
Lurasidone3Dan.gif
Systematic (IUPAC) name
(3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl]methyl}cyclohexyl)methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione
Clinical data
Trade namesLatuda
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa611016
Licence dataUS Daily Med:link
Pregnancy cat.B1 (AU) B (US)
Legal statusPrescription Only (S4) (AU) -only (CA) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability9–19% (oral)[1]
MetabolismHepatic (CYP3A4-mediated)[1]
Half-life18 hours[1]
ExcretionFaecal (~80%), renal (~9%)[1]
Identifiers
CAS number367514-87-2
ATC codeN05AE05
PubChemCID 213046
ChemSpider184739
UNII22IC88528T YesY
ChEBICHEBI:70735 YesY
ChEMBLCHEMBL1237021
SynonymsSM-13,496
Chemical data
FormulaC28H36N4O2S 
Mol. mass492.676 g/mol

Lurasidone /lɜr.ˈræ.sɪ.dn/ (trade name Latuda) is a new atypical antipsychotic developed by Dainippon Sumitomo Pharma[2] and marketed by Sunovion in the USA. In the USA, it is also approved for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults when used alone or in combination with lithium or valproate.

Medical uses[edit]

Lurasidone is FDA approved for the treatment of schizophrenia[3] and depressive episodes associated with bipolar I disorder.[4] It has not yet received regulatory approval in the UK. It received EMA approval on January 24, 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on October 15, 2012.[5] Switzerland is the first and only European country so far where lurasidone is approved for schizophrenia.

In July 2013 lurasidone received approval for bipolar I depression.[4] Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine,[6][7][8][9] olanzapine[10][11][12] and possibly asenapine[13]) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity,[14] which is yet to be clearly demonstrated for lurasidone.

Lurasidone may be useful for treating the cognitive and memory deficits seen in schizophrenia. In animal studies, it reversed dizocilpine-induced learning and memory impairment and was found to be superior in doing this to all of the other antipsychotics examined, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol.[15][16] Lurasidone has activity at several serotonin receptors that are involved in learning and memory, and unlike most other antipsychotics, lacks any anticholinergic effects (which are known to impair cognitive processes and memory).[15] These properties may underlie its improved effectiveness in treating these symptoms relative to older agents.[15]

Lurasidone has completed phase III clinical trial for extended use study in India,[17] although it is not yet approved in India.[citation needed] Lurasidone is not approved by the Food and Drug Administration (FDA) for the treatment of behavior disorders in older adults with dementia.

Adverse effects[edit]

Side effects are generally similar to other antipsychotics. The drug has a relatively well-tolerated side effect profile, with low propensity for QTc interval changes, weight and lipid-related adverse effects.[18] In a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone and aripiprazole).[19]

As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack;[20][21] however, these risks are not likely to be greater than those associated with antipsychotics of other classes.[22] Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with its use.[23]

Pharmacology[edit]

Pharmacodynamics[edit]

Lurasidone acts as an antagonist of the following sites:[15][24]

And as a partial agonist of the following sites:[15]

Note: All values are rounded to the nearest tenth.

It has only weak or negligible actions at the H1, and mACh receptors.[15]

Pharmacokinetics[edit]

Lurasidone is metabolized in the liver via the enzyme CYP3A4.[20] This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole or grapefruit juice, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin or St. John's wort can reduce plasma levels and consequently decrease the effects of the drug.

Chemical synthesis[edit]

The large scale synthesis of lurasidone began with the bis-mesylation of commercially available diol 1 to furnish disulfone 2.[25][26] Dialkylation of piperazine 3 with disulfone 2 under basic conditions afforded spirocyclic tetralkyl ammonium species 4. By subjecting tetralkyl ammonium salt 4 to basic conditions in the presence of succinimide 5 an interesting regioselective ring-opening alkylation reaction occurs to form the 1,2-trans-substituted cyclohexane motif of lurasidone.[27] Finally, exposure of lurasidone to hydrochloric acid provided the lurasidone hydrochloride salt.[28]

Synthetic route to lurasidone hydrochloride

References[edit]

  1. ^ a b c d "PRODUCT INFORMATION LATUDA (lurasidone hydrochloride)" (PDF). TGA eBusiness Services. Therapeutic Goods Administration. 16 April 2014. Retrieved 1 May 2014. 
  2. ^ Meyer, Jonathan M; Loebel, Antony D; Schweizer, Edward (2009). "Lurasidone: A new drug in development for schizophrenia". Expert Opinion on Investigational Drugs 18 (11): 1715–26. doi:10.1517/13543780903286388. PMID 19780705. 
  3. ^ "FDA approves Latuda to treat schizophrenia in adults" (Press release). USFDA. 2010-10-28. Retrieved October 29, 2010. 
  4. ^ a b Lowes R. Lurasidone Approved for Bipolar Depression [Internet]. Medscape. 2013 [cited 2013 Oct 2]. Available from: http://www.medscape.com/viewarticle/807204
  5. ^ http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_latuda_145406-eng.php#a2 Health Canada Summary Basis of Decision (SBD) for PrLATUDA™
  6. ^ Young, Allan H.; McElroy, Susan L.; Bauer, Michael; Philips, Nabil; Chang, William; Olausson, Bengt; Paulsson, Björn; Brecher, Martin; EMBOLDEN I (Trial 001) Investigators (2010). "A Double-Blind, Placebo-Controlled Study of Quetiapine and Lithium Monotherapy in Adults in the Acute Phase of Bipolar Depression (EMBOLDEN I)". The Journal of Clinical Psychiatry 71 (2): 150–62. doi:10.4088/JCP.08m04995gre. PMID 20122369. 
  7. ^ Suppes, Trisha; Datto, Catherine; Minkwitz, Margaret; Nordenhem, Arvid; Walker, Chris; Darko, Denis (2010). "Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression". Journal of Affective Disorders 121 (1–2): 106–15. doi:10.1016/j.jad.2009.10.007. PMID 19903574. 
  8. ^ "Corrigendum". Bipolar Disorders 10 (3): 451. 2008. doi:10.1111/j.1399-5618.2008.00585.x. 
  9. ^ Thase, ME (2008). "Quetiapine monotherapy for bipolar depression". Neuropsychiatric disease and treatment 4 (1): 11–21. doi:10.2147/ndt.s1162. PMC 2515925. PMID 18728771. 
  10. ^ Tohen, Mauricio; Vieta, E; Calabrese, J; Ketter, TA; Sachs, G; Bowden, C; Mitchell, PB; Centorrino, F; Risser, R; Baker, RW; Evans, AR; Beymer, K; Dube, S; Tollefson, GD; Breier, A (2003). "Efficacy of Olanzapine and Olanzapine-Fluoxetine Combination in the Treatment of Bipolar I Depression". Archives of General Psychiatry 60 (11): 1079–88. doi:10.1001/archpsyc.60.11.1079. PMID 14609883. 
  11. ^ Tohen, M.; Katagiri, H.; Fujikoshi, S.; Kanba, S. (2013). "Efficacy of olanzapine monotherapy in acute bipolar depression: A pooled analysis of controlled studies". Journal of Affective Disorders 149 (1–3): 196–201. doi:10.1016/j.jad.2013.01.022. PMID 23485111. 
  12. ^ Corya, Sara A.; Perlis, Roy H.; Keck Jr, Paul E.; Lin, Daniel Y.; Case, Michael G.; Williamson, Doug J.; Tohen, Mauricio F. (2006). "A 24-Week Open-Label Extension Study of Olanzapine-Fluoxetine Combination and Olanzapine Monotherapy in the Treatment of Bipolar Depression". The Journal of Clinical Psychiatry 67 (5): 798–806. doi:10.4088/JCP.v67n0514. PMID 16841630. 
  13. ^ Azorin, J.M.; Sapin, C.; Weiller, E. (2013). "Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: Results from post hoc analyses". Journal of Affective Disorders 145 (1): 62–9. doi:10.1016/j.jad.2012.07.013. PMID 22868059. 
  14. ^ Cipriani, Andrea; Barbui, Corrado; Salanti, Georgia; Rendell, Jennifer; Brown, Rachel; Stockton, Sarah; Purgato, Marianna; Spineli, Loukia M; Goodwin, Guy M; Geddes, John R (2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: A multiple-treatments meta-analysis". The Lancet 378 (9799): 1306–15. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976. 
  15. ^ a b c d e f Ishiyama, Takeo; Tokuda, Kumiko; Ishibashi, Tadashi; Ito, Akira; Toma, Satoko; Ohno, Yukihiro (2007). "Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test". European Journal of Pharmacology 572 (2–3): 160–70. doi:10.1016/j.ejphar.2007.06.058. PMID 17662268. 
  16. ^ Enomoto, T; Ishibashi, T; Tokuda, K; Ishiyama, T; Toma, S; Ito, A (2008). "Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats". Behavioural Brain Research 186 (2): 197–207. doi:10.1016/j.bbr.2007.08.012. PMID 17881065. 
  17. ^ "Lurasidone Extended Use Study". ClinicalTrials.gov. 
  18. ^ Dainippon Sumitomo Pharma (August 26, 2009). "Lurasidone Demonstrated Efficacy in Treating Patients with Schizophrenia in Pivotal Phase III Study". [dead link]
  19. ^ Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.". Lancet 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.  edit
  20. ^ a b "Latuda: Prescribing Information". Psychotherapeutic Drugs. Retrieved 2010-12-17. 
  21. ^ "Latuda". Drugs.com. Retrieved 2010-12-17. 
  22. ^ Herrmann, N.; Mamdani, M; Lanctôt, KL (2004). "Atypical Antipsychotics and Risk of Cerebrovascular Accidents". American Journal of Psychiatry 161 (6): 1113–5. doi:10.1176/appi.ajp.161.6.1113. PMID 15169702. 
  23. ^ Sunovion Pharmaceuticals. "Latuda Prescribing Information". Latuda.com. Retrieved 25 March 2014. 
  24. ^ Ishibashi, T.; Horisawa, T.; Tokuda, K.; Ishiyama, T.; Ogasa, M.; Tagashira, R.; Matsumoto, K.; Nishikawa, H.; Ueda, Y.; Toma, S.; Oki, H.; Tanno, N.; Saji, I.; Ito, A.; Ohno, Y.; Nakamura, M. (2010). "Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity". Journal of Pharmacology and Experimental Therapeutics 334 (1): 171–81. doi:10.1124/jpet.110.167346. PMID 20404009. 
  25. ^ Ding, Hong X.; Liu, Kevin K.-C.; Sakya, Subas M.; flick, Andrew C.; O'Donnell, Christopher J. (6 April 2013). "Synthetic approaches to the 2011 new drugs". Bioorganic & Medicinal Chemistry (elsevier) 21: 2795–2825. doi:10.1016/j.bmc.2013.02.061. 
  26. ^ JP 2006282527, YAGI HIDEKI; KODERA TAKAHIRO; KURUMAYA MASAHIKO; TANAKA KAZUYUKI, "CYCLOHEXANE DERIVATIVE AND METHOD FOR PRODUCING THE SAME", published 2006-10-19 
  27. ^ US patent 20110263847, Ae Nobuyuki and Fujiwara Yuji, "Process of a Quaternary Ammonium Salt", issued 2011-10-27 
  28. ^ WO 2005009999, KAKIYA YUZO; ODA MAYUMI, "PROCESS FOR PRODUCING IMIDE COMPOUND", published 2005-02-03