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

1. Tanta University Senior Student
Faculty of Pharmacy Drug Design Course
Pharmaceutical 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 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 7637
Under Supervision of :
Dr/ Eman El-Bastawisy
Dr/ Mervat El-Hamamsy
Ph/ Salma El-Sherbiny

2. 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 :

3. 7- Production : chemical synthesis.
8- Type ( Break Through, Me Too, New Indication, Others ):
Me too
9- 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) 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 memory
2) 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,

4. 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

5. 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.

6. 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.

7. Serotonin 5HT-2A receptor antagonism :

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[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 oral
administered 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.

9. 15- Structures , Generic name(s) & Brand name(s) of related drugs :
Generic Name Brand Name Structure
Chloropromazine 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)

10. 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.

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 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.org
www.fda.gov
www.Latuda.com
www.latudahcp.com
www.medscape.com
www.chemspider.com
www.Drugbank.ca
www.chemdrug.com
www.dailymed.nlm.nih.gov
Journals :
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 )