Tanta University Senior StudentFaculty of Pharmacy Drug Design CoursePharmaceutical Chemistry Department 2011/2012

(Human Health Care Products introduced during 2011)

Student group number : 92

Generic / INN Name : Lurasidone

Brand Name : Latuda®

Chemical Structure :

Names of Student group in serial roll :Student name Serial roll

1- Abdelrahman Wageeh Ahmed 76312- Abdelaziz Fahmy Abdelaziz 76323- Abdelghany Hamed Abdelghany 76334- Abdelfatah Magdy Abdelfatah 76345- Abdullah Abdelnaby Hassan 76356-Abdullah Essam Mohamed 76367-Abdullah Mohsen Ragheb 7637

Under Supervision of :

Dr/ Eman El-BastawisyDr/ Mervat El-HamamsyPh/ Salma El-Sherbiny

1- Generic / INN Name : Lurasidone

2- 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 # : 367514-88-3

5- Innovative Company & ( Country ) :

Dainippon Sumitomo Pharma Co., Ltd.Which is a pharmaceutical company based in Japan. Its headquarters are in Chuo-ku, Osaka.

Current Manufacturer is Sunovion Pharmaceuticals.

6- Chemical Structure :

7- Production : chemical synthesis.

8- Type ( Break Through, Me Too, New Indication, Others ): Me too

9- Class ( ATC Coding System ) : N05AHN Nervous SystemN05 PsycholepticsN05A AntipsychoticsN05AH Diazepines , Oxazepines , Thiazepines , Oxepines.

10- Indications :Lurasidone is the newest atypical antipsychotic (AA) agent

approved for the treatment of schizophrenia in adults. In clinical studies, Lurasidone alleviates positive (e.g., hallucinations, delusions) without inducing extra pyramidal side effects except for akathisia , despite its potent D2 antagonistic actions. Clinical evidence of Lurasidone's effect on negative symptoms of schizophrenia has yet to establish efficacy.Lurasidone may be useful for treating cognitive and memory deficits seen in schizophrenia for several reasons:1) unlike many other antipsychotics, Lurasidone does not block the

muscarinic acetylcholine receptors, an action well-known to impair learning and memory2) Lurasidone has prominent activity at 5-HT1A, 5-HT2A, 5-HT7, and α2C-adrenergic receptors, all of which have been implicated in enhancement of cognitive function if modulated properly. In animal studies,

Lurasidone was found to be superior to all of the other antipsychotics examined in reversing dizocilpine-induced learning and memory impairment, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol.

11- Dosage Form(s) & Presentation(s) :Lurasidone is available in 40-mg and 80-mg tablets. The

recommended starting dose is 40 mg once daily, with a maximum dose of 80 mg/day. Higher doses provide no additional benefit and increase the incidence of certain adverse reactions. The dosage should not exceed 40 mg/day in patients with moderate-to-severe renal or hepatic impairment or in patients taking a moderate CYP3A4 inhibitor. Patients taking strong CYP3A4 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 having efficacy in schizophrenia, is unknown. It has been suggested that the

efficacy of LATUDA in schizophrenia is mediated through a combination of central dopamine D2 and serotonin 5HT-2A receptor antagonism.

In vitro receptor binding of LATUDA

The correlation between receptor binding affinities and clinical outcomes is 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. These receptors are known to improve cognitive capabilities upon effective regulation. The drug has limited affinity for histamine-1 and acetylcholine- M1 receptors and is a partial agonist for the serotonin 5-hydroxytryptamine (5HT)1A receptor. Lurasidone enhances the functions of muscarinic acetylcholine receptors, which are known to aid in memory and learning functions.

The dopamine D2-, D3-, D4 receptor

There are two main subgroups of dopamine receptor – D1-like and D2-like. The D2-like family contains the D2, D3 and D4 subtypes and the D1-like receptor family contains the D1 and D5 receptor subtypes. The D2-like receptors are found throughout the brain and in smooth muscle and presynaptic nerve terminals. Coupled to inhibitory G-proteins, dopamine D2-like receptors have an inhibitory effect on neurotransmission when bound by an agonist. Many neuroleptic drugs are antagonists of the D2 receptors. This class of drug is used to treat psychotic disorders, such as schizophrenia.

D2 receptor antagonist

A D2 receptor antagonist prevents the activation of the dopamine D2 receptor. The D2 receptor is coupled to inhibitory G-proteins, which dissociate from the receptor on agonist binding and inhibit secondary messenger signaling mechanisms. This causes inhibition of down-stream signaling mechanisms. Antagonist binding inhibits this usual process, resulting in cell depolarization.

Serotonin 5HT-2A receptor antagonism :

13- Pharmacophoric group :

(1R,2S,6R,7S)-4-{[(1R,2R)-2-{[4-(1,2-Benzothiazol-3-yl)-1-piperazinyl]methyl}cyclohexyl]methyl}-4-azatricyclo[5.2.1.02,6]decane-3,5-dione , structure shows 6 stereocenters that have major influence on its action as atypical antipsychotic drug .

14- Expected ADME Profile :

- Absorption Lurasidone is absorbed and reaches highest concentration in 1-3

hours. Nine to 19 percent of oraladministered dose is absorbed into the system. Its level is enhanced with food consumption.Cmax and AUC are increased by 3-times and 2-times, respectively, in the presence 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.

15- Structures , Generic name(s) & Brand name(s) of related drugs :

Generic Name Brand Name StructureChloropromazine Largactil®

(Sanofi Aventis) , Thorazine®(GlaxoSmithKline

Haloperidol Haldol®(Janssen Pharm) ,Serenace®(Pfizer)

Quetiapine Seroquel®(Sun Pharma)

Clozapine Clozaril®(Novartis)

Olanzapine Zyprexa®(Eli Lilly)

Aripiprazole Abilify ®(Bristol Myers Squibb)

16- SAR of drug relative to other available drugs for the same indication :

Lurasidone is a chiral benzoisothiazol derivative - the benzoisothiazol is the fused five-six dual ring structure on the right of the figure. Its structure contains an imide heterocyclic and a piperazine functional group. The central piperazine nitrogen is basic. The chemical structure, properties and pharmacology are similar to Ziprasidone.

17- Advantages & Disadvantages of Drugs relative to other available drugs :- 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 – Related Psychosis (a severe mental health problem) . An increased risk for stroke and mini stroke has been reported in elderly people with dementia-related psychosis.- Neuroleptic malignant syndrome (NMS):

High fever; stiff muscles; confusion; changes in pulse, heart rate, or blood pressure; sweating; or muscle pain and weakness. Treatment should be stopped if you have NMS. - Tardive dyskinesia (TD): TD is a serious and sometimes permanent side effect reported with LATUDA and similar medicines. TD includes uncontrollable movements of the face, tongue, and other parts of the body. The risk for developing TD and the chance that it will become permanent is thought to increase the longer a person takes the medicine and the more medicine a person takes over time. TD can develop after a person 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 the medicine.

- 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 atypical

antipsychotic drug in the upcoming new years . Latuda binding to receptor may be enhanced to gain more efficiency and potency , may some modification make more potent drug and modify the partial agonist activity of the drug on the serotonin 5-hydroxytryptamine (5HT)1A receptor . Additional research is running to help developing the drug as third 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 www.Latudahcp.com )