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Latuda (Lurasidone)


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This is my Drug Design assignment with my pharmacy colleagues in last year of our study in college ...
its private .. so don't read it :P

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Latuda (Lurasidone)

  1. 1. Tanta University Senior StudentFaculty of Pharmacy Drug Design CoursePharmaceutical Chemistry Department 2011/2012 (Human Health Care Products introduced during 2011)Student group number : 92Generic / INN Name : LurasidoneBrand Name : Latuda®Chemical Structure :Names of Student group in serial roll : Student name Serial roll 1- Abdelrahman Wageeh Ahmed 7631 2- Abdelaziz Fahmy Abdelaziz 7632 3- Abdelghany Hamed Abdelghany 7633 4- Abdelfatah Magdy Abdelfatah 7634 5- Abdullah Abdelnaby Hassan 7635 6-Abdullah Essam Mohamed 7636 7-Abdullah Mohsen Ragheb 7637Under Supervision of : Dr/ Eman El-Bastawisy Dr/ Mervat El-Hamamsy Ph/ Salma El-Sherbiny
  2. 2. 1- Generic / INN Name : Lurasidone2- Brand Name : Latuda®3- Chemical 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 .4- CASR # : 367514-88-35- Innovative Company & ( Country ) :  Dainippon Sumitomo Pharma Co., Ltd.Which is a pharmaceutical company based in Japan. Its headquarters arein Chuo-ku, Osaka.  Current Manufacturer is Sunovion Pharmaceuticals.6- Chemical Structure :
  3. 3. 7- Production : chemical synthesis.8- Type ( Break Through, Me Too, New Indication, Others ): Me too9- Class ( ATC Coding System ) : N05AH N Nervous System N05 Psycholeptics N05A Antipsychotics N05AH Diazepines , Oxazepines , Thiazepines , Oxepines.10- Indications : Lurasidone is the newest atypical antipsychotic (AA) agentapproved for the treatment of schizophrenia in adults. In clinical studies,Lurasidone alleviates positive (e.g., hallucinations, delusions) withoutinducing extra pyramidal side effects except for akathisia , despite itspotent D2 antagonistic actions. Clinical evidence of Lurasidones effect onnegative symptoms of schizophrenia has yet to establish efficacy.Lurasidone may be useful for treating cognitive and memory deficits seenin schizophrenia for several reasons: 1) unlike many other antipsychotics, Lurasidone does not block themuscarinic acetylcholine receptors, an action well-known to impairlearning and memory2) Lurasidone has prominent activity at 5-HT1A, 5-HT2A, 5-HT7, and α2C-adrenergic receptors, all of which have been implicated in enhancementof cognitive function if modulated properly. In animal studies,
  4. 4. Lurasidone was found to be superior to all of the other antipsychoticsexamined in reversing dizocilpine-induced learning and memoryimpairment, including risperidone, olanzapine, quetiapine, clozapine,aripiprazole, and haloperidol.11- Dosage Form(s) & Presentation(s) : Lurasidone is available in 40-mg and 80-mg tablets. Therecommended starting dose is 40 mg once daily, with a maximum dose of80 mg/day. Higher doses provide no additional benefit and increase theincidence of certain adverse reactions. The dosage should not exceed 40mg/day in patients with moderate-to-severe renal or hepatic impairmentor in patients taking a moderate CYP3A4 inhibitor. Patients taking strongCYP3A4 inhibitors or inducers should not take Lurasidone.12- Chemical Mode of action at receptor site : Receptor Binding Profile :Proposed mechanism of action of LATUDA* The lower the Ki Value, The higher the affinity.The mechanism of action of LATUDA, as with other drugs havingefficacy in schizophrenia, is unknown. It has been suggested that the
  5. 5. efficacy of LATUDA in schizophrenia is mediated through a combinationof central dopamine D2 and serotonin 5HT-2A receptor antagonism. In vitro receptor binding of LATUDAThe correlation between receptor binding affinities and clinical outcomesis uncertain . Lurasidone is an isoindole derivative that has a unique receptor-binding profile with high affinity for dopamine-2, serotonin- 2A,serotonin-7, serotonin-1A, and noradrenaline-2C receptors. Thesereceptors are known to improve cognitive capabilities upon effectiveregulation. The drug has limited affinity for histamine-1 andacetylcholine- M1 receptors and is a partial agonist for the serotonin 5-hydroxytryptamine (5HT)1A receptor. Lurasidone enhances the functionsof muscarinic acetylcholine receptors, which are known to aid in memoryand learning functions.
  6. 6. The dopamine D2-, D3-, D4 receptor There are two mainsubgroups of dopamine receptor– D1-like and D2-like. The D2-like family contains the D2, D3and D4 subtypes and the D1-likereceptor family contains the D1and D5 receptor subtypes. TheD2-like receptors are foundthroughout the brain and insmooth muscle and presynapticnerve terminals. Coupled toinhibitory G-proteins, dopamineD2-like receptors have aninhibitory effect onneurotransmission when boundby an agonist. Many neurolepticdrugs are antagonists of the D2receptors. This class of drug is used to treat psychotic disorders, such asschizophrenia.D2 receptor antagonist A D2 receptorantagonist preventsthe activation of thedopamine D2receptor. The D2receptor is coupledto inhibitory G-proteins, whichdissociate from thereceptor on agonistbinding and inhibitsecondary messenger signaling mechanisms. This causes inhibition ofdown-stream signaling mechanisms. Antagonist binding inhibits thisusual process, resulting in cell depolarization.
  7. 7. Serotonin 5HT-2A receptor antagonism :
  8. 8. 13- Pharmacophoric group : (1R,2S,6R,7S)-4-{[(1R,2R)-2-{[4-(1,2-Benzothiazol-3-yl)-1-piperazinyl]methyl}cyclohexyl]methyl}-4-azatricyclo[,6]decane-3,5-dione , structure shows 6 stereocenters that have major influence onits action as atypical antipsychotic drug .14- Expected ADME Profile :- Absorption Lurasidone is absorbed and reaches highest concentration in 1-3hours. Nine to 19 percent of oraladministered dose is absorbed into the system. Its level is enhanced withfood consumption.Cmax and AUC are increased by 3-times and 2-times, respectively, in thepresence of food.- Distribution 98.8% of Lurasidone molecules is bound to plasma protein .- Metabolism Lurasidone is metabolized by CYP3A4 via oxidative N-dealkylation, hydroxylation and S oxidation.Major metabolites include two active and two non-active forms.- Elimination 80% is excreted in feces and 9% in urine.
  9. 9. 15- Structures , Generic name(s) & Brand name(s) of related drugs :Generic Name Brand Name StructureChloropromazine Largactil® (Sanofi Aventis) , Thorazine® (GlaxoSmithKlineHaloperidol Haldol® (Janssen Pharm) , Serenace® (Pfizer)Quetiapine Seroquel® (Sun Pharma)Clozapine Clozaril® (Novartis)Olanzapine Zyprexa® (Eli Lilly)Aripiprazole Abilify ® (Bristol Myers Squibb)
  10. 10. 16- SAR of drug relative to other available drugs for the sameindication : Lurasidone is a chiral benzoisothiazol derivative - thebenzoisothiazol is the fused five-six dual ring structure on the right of thefigure. Its structure contains an imide heterocyclic and a piperazinefunctional group. The central piperazine nitrogen is basic. The chemicalstructure, properties and pharmacology are similar to Ziprasidone.17- Advantages & Disadvantages of Drugs relative to other availabledrugs :- Favorable efficacy and safety profile than other antischizophrenic drugs.- LATUDA is contraindicated with strong CYP3A4 inhibitors (e.g.,ketoconazole) and strong CYP3A4 inducers (e.g., rifampin).- Increased Mortality in elderly patients with Dementia – RelatedPsychosis (a severe mental health problem) . An increased risk for strokeand mini stroke has been reported in elderly people with dementia-relatedpsychosis.- Neuroleptic malignant syndrome (NMS): High fever; stiff muscles; confusion; changes in pulse, heart rate,or blood pressure; sweating; or muscle pain and weakness. Treatmentshould be stopped if you have NMS.- Tardive dyskinesia (TD): TD is a serious and sometimes permanentside effect reported with LATUDA and similar medicines. TD includesuncontrollable movements of the face, tongue, and other parts of thebody. The risk for developing TD and the chance that it will becomepermanent is thought to increase the longer a person takes the medicineand the more medicine a person takes over time. TD can develop after aperson has been taking the medicine for a short time at low doses,although this is much less common. There is no known treatment for TD,but it may go away partially or completely if the person stops taking themedicine.
  11. 11. - Metabolic changes :a) High blood sugar.b) High cholesterol and triglycerides.c) Weight gain.18 Future Outlook : Latuda is predicted to be the number one selling atypicalantipsychotic drug in the upcoming new years . Latuda binding toreceptor may be enhanced to gain more efficiency and potency , maysome modification make more potent drug and modify the partial agonistactivity of the drug on the serotonin 5-hydroxytryptamine (5HT)1Areceptor . Additional research is running to help developing the drug asthird generation atypical antipsychotic drug.19- References :www.wikipedia.orgwww.fda.govwww.Latuda.comwww.latudahcp.comwww.medscape.comwww.chemspider.comwww.Drugbank.cawww.chemdrug.comwww.dailymed.nlm.nih.govJournals :NDA Application number (200603) Medical Reviews.NDA Application number (200603) Chemical Reviews.NDA Application number (200602) Proprietay Name Reviews.Latuda Prescribing Information ( Available on )