**6. Repositioned drugs**

Drug repositioning is an alternative approach to traditional drug discovery. With increasing market demand many pharmaceutical companies are developing new drugs or new therapeutic uses from existing/old/available drugs by drug repositioning approaches in less time, yet at low cost. In drug discovery program, the repositioning is usually essentially carried out in two stages as described follows. In the first stage, the *in silico* screening of approved drugs against a particular disease target is carried out, which is followed by the second step, in which the selected identified molecules are further experimentally investigated both *in vitro* and *in vivo* in specific disease models of interest. After successful preclinical studies in the

second stage of repositioning, identified drug candidates enter the clinical trials in human subjects [24, 25]. **Figure 5** delineates several potential strategies (with suitable examples) of drug repositioning.

**Table 3** depicts examples of some repositioned drugs already developed or currently under development from various approved (FDA) or marketed drugs and investigational new drugs (IND). Some repositioned drugs currently under clinical trials in COVID-19 are also included in the list.

Colchicine, a well-known anti-inflammatory drug used in the treatment of gout and pericarditis, is currently under clinical trial for treating COVID-19 patients. This drug has been proved to be effective in preventing massive cytokine storm induced pneumonia caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). The antiviral effect of an older antimalarial drug, chloroquine (used as phosphate salt) against SARS-CoV-2 infection has also been investigated worldwide. Studies suggest that chloroquine may be beneficial in preventing coronavirus induced pneumonia in COVID-19. As per recent reports from NIH (National Institutes of Health, US), the clinical trial of a combination of hydroxychloroquine/azithromycin for the treatment of COVID-19 patients has already been started. In this combination, both the drugs are FDA approved, where hydroxychloroquine is an antimalarial drug and azithromycin is an antibacterial antibiotic. An anti-viral drug, favipiravir intended for the treatment of influenza is currently under phase-2/phase-3 clinical trials on COVID-19 patients around the world (China, Japan, US, India). Glenmark has initiated phase-3 trial on favipiravir for the treatment of COVID-19 patients in India. An investigational anti-retroviral drug called remdesivir (originally developed by Gilead Sciences Inc. for the treatment of Ebola, but failed in clinical trial) is also under clinical trial for treating COVOD-19 patients in several countries like China, US, UK and India. In India, clinical trials on favipiravir, remdesivir and colchicine are currently underway by CSIR (Council of Scientific & Industrial Research) laboratories. A fixed dose drug combination called lopinavir/ritonavir earlier approved

#### **Figure 5.**

*Strategies of drug repositioning with examples. vHTS: virtual high-throughput screening; HTS/HCS: high-throughput and/or high-content screening; Strategy 1 (S1): serendipitous observation; Strategy 2 (S2): observance of novel activity (specific disease phenotype, rational approach); Strategy 3 (S3): new drug-target interaction; Strategy 4 (S4): new roles for existing protein target; Strategy 5 (S5): new biochemical pathways; Strategy 6 (S6): disease-specific repositioning; Strategy 7 (S7): unexpected side effects.*

**13**

*Drug Repurposing (DR): An Emerging Approach in Drug Discovery*

the treatment of patients with COVID-19 [25, 26].

**Drug, pharmacological** 

Amphotericin B (AMB), Anti-fungal antibiotic

**category**

Astemizole, Anti-histaminic

Atomoxetine, Anti-depressant

Azithromycin, Antibacterial antibiotic

Bupropion, SSRI, Anti-depressant

NSAID

antagonist

Colchicine, Antiinflammatory agent

Dimethyl fumarate, Anti-allergic

Disulfiram, Acetaldehyde dehydrogenase inhibitor

Bromocriptine, Dopamine receptor antagonist

Celecoxib, COX-2 inhibitor,

Cimetidine, H2 receptor

to treat HIV/AIDS under the brand name *Kaletra* is currently being studied to treat COVID-19 patients in several countries. This drug combination was investigated along with the flu drug, oseltamivir (Tamiflu) to cure infection caused by SARS-CoV-2 in Thailand. The clinical trial of an anti-parasitic drug called ivermectin (used traditionally as an approved treatment in worm infestations) for the treatment of COVID-19 is being undertaken in several parts of the world after a successful *in vitro* effectiveness against SARS-CoV-2 infection at Monash University in Melbourne, Australia. The clinical trial of toclizumab, an IL-6 receptor antagonist (marketed under the brand name *Actemra*) used for the treatment of inflammatory illness such as rheumatoid arthritis is also being conducted for

**Original indication New indication Status of** 

Aspirin, NSAID Pain and inflammation CVDs (Anti-platelet) Already developed\*

Amantadine, Anti-viral Influenza PD Already developed\*

Depression Attention deficit,

Inflammation Breast and colon

Chloroquine, Anti-malarial Malaria COVID-19 Under development\*

Daunorubicin, Antibiotic Breast cancer Already developed\*

Psoriasis Multiple sclerosis

(MS)

clinical trial for ALCL)

Gastric ulcer Breast, lung and

Allergic illness such as

urticaria

Elephantiasis

Avermectin, Anthelmintic River blindness,

Crizotinib, ALK inhibitor Lymphoma (under

Digoxin, Cardiotonic CVDs such as heart

failure

Fungal infections Leishmaniasis Already developed\*

Hyperactivity disorder

Bacterial infections COVID-19 Under development\*

PD DM (type 2) Under development\*

Depression Smoking cessation Already developed\*

prostate cancer

Gout (Gouty arthritis) Pericarditis Already developed\*

Chronic alcoholism Cancer Under development\*

cancer

**development**

Already developed\*

Under development\*

Under development\*

Already developed\*

Prostate cancer Under development\*

Malaria Under development\*

Tuberculosis Under development\*

NSCLC Already developed#

COVID-19 Under development\*

Prostate Cancer Under development\*

*DOI: http://dx.doi.org/10.5772/intechopen.93193*

### *Drug Repurposing (DR): An Emerging Approach in Drug Discovery DOI: http://dx.doi.org/10.5772/intechopen.93193*

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

suitable examples) of drug repositioning.

trials in COVID-19 are also included in the list.

second stage of repositioning, identified drug candidates enter the clinical trials in human subjects [24, 25]. **Figure 5** delineates several potential strategies (with

**Table 3** depicts examples of some repositioned drugs already developed or currently under development from various approved (FDA) or marketed drugs and investigational new drugs (IND). Some repositioned drugs currently under clinical

Colchicine, a well-known anti-inflammatory drug used in the treatment of gout and pericarditis, is currently under clinical trial for treating COVID-19 patients. This drug has been proved to be effective in preventing massive cytokine storm induced pneumonia caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). The antiviral effect of an older antimalarial drug, chloroquine (used as phosphate salt) against SARS-CoV-2 infection has also been investigated worldwide. Studies suggest that chloroquine may be beneficial in preventing coronavirus induced pneumonia in COVID-19. As per recent reports from NIH (National Institutes of Health, US), the clinical trial of a combination of hydroxychloroquine/azithromycin for the treatment of COVID-19 patients has already been started. In this combination, both the drugs are FDA approved, where hydroxychloroquine is an antimalarial drug and azithromycin is an antibacterial antibiotic. An anti-viral drug, favipiravir intended for the treatment of influenza is currently under phase-2/phase-3 clinical trials on COVID-19 patients around the world (China, Japan, US, India). Glenmark has initiated phase-3 trial on favipiravir for the treatment of COVID-19 patients in India. An investigational anti-retroviral drug called remdesivir (originally developed by Gilead Sciences Inc. for the treatment of Ebola, but failed in clinical trial) is also under clinical trial for treating COVOD-19 patients in several countries like China, US, UK and India. In India, clinical trials on favipiravir, remdesivir and colchicine are currently underway by CSIR (Council of Scientific & Industrial Research) laboratories. A fixed dose drug combination called lopinavir/ritonavir earlier approved

*Strategies of drug repositioning with examples. vHTS: virtual high-throughput screening; HTS/HCS: high-throughput and/or high-content screening; Strategy 1 (S1): serendipitous observation; Strategy 2 (S2): observance of novel activity (specific disease phenotype, rational approach); Strategy 3 (S3): new drug-target interaction; Strategy 4 (S4): new roles for existing protein target; Strategy 5 (S5): new biochemical pathways;* 

*Strategy 6 (S6): disease-specific repositioning; Strategy 7 (S7): unexpected side effects.*

**12**

**Figure 5.**

to treat HIV/AIDS under the brand name *Kaletra* is currently being studied to treat COVID-19 patients in several countries. This drug combination was investigated along with the flu drug, oseltamivir (Tamiflu) to cure infection caused by SARS-CoV-2 in Thailand. The clinical trial of an anti-parasitic drug called ivermectin (used traditionally as an approved treatment in worm infestations) for the treatment of COVID-19 is being undertaken in several parts of the world after a successful *in vitro* effectiveness against SARS-CoV-2 infection at Monash University in Melbourne, Australia. The clinical trial of toclizumab, an IL-6 receptor antagonist (marketed under the brand name *Actemra*) used for the treatment of inflammatory illness such as rheumatoid arthritis is also being conducted for the treatment of patients with COVID-19 [25, 26].



**15**

**Table 3.**

*\**

*#*

*Drug Repurposing (DR): An Emerging Approach in Drug Discovery*

**Original indication New indication Status of** 

Psychiatric illness Breast cancer Under development\*

Cancers like leukemias and lymphomas

syndrome

Pancreatic neuroendocrine tumors

NTDs like Leishmaniasis (in combination with miltefosine)

Leprosy

Systemic lupus erythematosus

Multiple myeloma,

RA COVID-19 Under development\*

(bipolar disorder), migraine headache

AD Already developed\*

HIV/AIDS Already developed#

CVDs Lung cancer Already developed\*

Orlistat, Anti-obesity agent Obesity Cancer Already developed\*

Propranolol, β-Blocker Hypertension Migraine Already developed\*

Retinoic acid Acne Acute leukemia Already developed\*

PD Restless leg

(failed in clinical trial)

as RSV, hepatitis C infections

Pulmonary arterial hypertension

Imatinib-resistant GIST, RCC

Breast cancer, Anticancer

Immunomodulation, Morning sickness (withdrawn)

Hypertension, Heart

*AD: Alzheimer's disease; AChE: acetylcholine esterase inhibitor; ALCL: anaplastic large cell lymphoma; ALL: acute lymphocytic leukemia; ALK: anaplastic lymphoma kinase; ARB: angiotensin-receptor blocker; CML: chronic myeloid leukemia; COVID-19: coronavirus diseases-19; COX: cyclooxygenase; CVDs: cardiovascular diseases; DM: diabetes mellitus; GIST: gastrointestinal stromal tumor; HIV/AIDS: human immunodeficiency virus/acquired immunodeficiency syndrome; IBD: inflammatory bowel disease; IL: interleukin; NSAID: non-steroidal antiinflammatory drug; NSCLC: non-small cell lung carcinoma; NTD: neglected tropical diseases; PD: Parkinson's diseases; PDE: phosphodiesterase; RA: rheumatoid arthritis; RCC: renal cell carcinoma; RSV: respiratory syncytial virus; SSNRI: selective serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor;* 

attack

trial)

*Examples of some repositioned drugs from approved and investigational drugs [24–29].*

*Indicates successful repositioning from investigational new drug (IND).*

Zidovudine, Anti-viral Cancer (failed clinical

*Indicates successful repositioning from FDA approved drug.*

*TKI: tyrosine kinase inhibitor; UTI: urinary tract infections.*

Topiramate Fungal infections IBD Already developed\*

Epilepsy Manic depression

**development**

Under development\*

Already developed\*

Already developed\*

Already developed\*

Under development\*

Already developed#

Already developed\*

COVID-19 Under development#

Erectile dysfunction Already developed\*

*DOI: http://dx.doi.org/10.5772/intechopen.93193*

Remdesivir, Anti-viral Influenza, Ebola

Ribavirin, Anti-viral Viral infection such

Sildenafil, PDE inhibitor Angina pectoris,

**Drug, pharmacological** 

Penfluridol/Pimozide, Anti-psychotics

**category**

Ritoximab Ropinirole, Anti-Parkinsonian drug

Simvastatin, Hypolipidemic

Sunitinib, TKI (Anti-cancer)

(Anti-cancer)

modulator

Valproic acid, Anti-epileptic

Valsartan, ARB (Anti-hypertensive)

Tamoxifen, Anti-estrogen

Thalidomide, Immune

Tocilizumab, IL-6 inhibitor (Immune modulator)

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

Duloxetine, SSNRI Depression Generalized

**Original indication New indication Status of** 

Immune suppressant Pancreatic

Favipiravir, Anti-viral Influenza COVID-19 Under development\*

Depression Premenstrual

Gabapentin, Anti-epileptic Epilepsy Neuropathic pain Already developed\*

Neuromuscular paralysis

Isoniazid, Anti-tubercular Tuberculosis Certain types of

Itraconazole, Anti-fungal Fungal infections Cancer like NSCLC

Scabies, river blindness, helminthiasis

Metformin, Anti-diabetic DM (type 2) Breast and colon

Termination of pregnancy in combination with misoprostol

Nelfinavir, Anti-viral HIV/AIDS Breast cancer,

Nitroxoline, Anti-bacterial UTI Breast, bladder and

anxiety disorder, fibromyalgia, chronic musculoskeletal pain, neuropathic pain

neuroendocrine tumors

Cancer Breast cancer Already developed\*

Malaria, RA COVID-19 Under development\*

Asthma Neuropathic pain Already developed\*

CML, ALL GIST Already developed\*

(Anti-angiogenic)

HIV/AIDS COVID-19 Under development\*

Cancer, CVDs

Cancer Psoriasis, RA Already developed\*

Depression Fibromyalgia Already developed\*

Amoeba infection

Hypertension Androgenic alopecia Already developed\*

NSCLC (under clinical trials)

pancreatic cancers

Cancer Leishmaniasis,

tumor

dysphoria

**development**

Already developed\*

Already developed\*

Already developed\*

Already developed\*

Under development\*

Under development\*

Already developed\*

Under development\*

Under development\*

AD Already developed\*

COVID-19 Under development\*

Cushing's syndrome Already developed\*

**Drug, pharmacological** 

Everolimus, Immune suppressant

Fluorouracil, Antimetabolite, Anti-cancer

Fluoxetine, Anti-depressant

inhibitor

Imatinib, TKI (Anti-cancer)

Galantamine, AChE

Hydroxychloroquine, Anti-malarial

Ibudilast, PDE inhibitor (Anti-asthmatic)

Ivermectin, Anthelmintic (Anti-parasitic)

Lopinavir/Ritonavir,

Methotrexate, Antimetabolite (Anti-cancer)

Milnacipram, Anti-depressant

Miltefosine, Anti-leishmanial

Mifepristone, Antiprogestin

Minoxidil, Vasodilator (Anti-hypertensive)

Anti-viral

**category**

**14**


*\* Indicates successful repositioning from FDA approved drug.*

*# Indicates successful repositioning from investigational new drug (IND).*

*AD: Alzheimer's disease; AChE: acetylcholine esterase inhibitor; ALCL: anaplastic large cell lymphoma; ALL: acute lymphocytic leukemia; ALK: anaplastic lymphoma kinase; ARB: angiotensin-receptor blocker; CML: chronic myeloid leukemia; COVID-19: coronavirus diseases-19; COX: cyclooxygenase; CVDs: cardiovascular diseases; DM: diabetes mellitus; GIST: gastrointestinal stromal tumor; HIV/AIDS: human immunodeficiency virus/acquired immunodeficiency syndrome; IBD: inflammatory bowel disease; IL: interleukin; NSAID: non-steroidal antiinflammatory drug; NSCLC: non-small cell lung carcinoma; NTD: neglected tropical diseases; PD: Parkinson's diseases; PDE: phosphodiesterase; RA: rheumatoid arthritis; RCC: renal cell carcinoma; RSV: respiratory syncytial virus; SSNRI: selective serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TKI: tyrosine kinase inhibitor; UTI: urinary tract infections.*

#### **Table 3.**

*Examples of some repositioned drugs from approved and investigational drugs [24–29].*
