Repositioning Drugs

 

Dr. T. Naga Ravi Kiran**, A. V. S Madhulatha*, Dr. J. N. Suresh Kumar*, P. Udaya Sri*

Department of Pharmacy, Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopeta. A P.

*Corresponding Author E-mail:

 

ABSTRACT:

Drug repositioning is the application of already approved drugs and compounds to treat a different disease. New drug discovery is a very time consuming and cost effective so alternative approach is old drug repositioning for new indications. Drug repositioning is also known as recycling, repurposing and re-tasking. Drug repurposing is an approach to finding new uses for older drugs and has been gaining popularity in recent years. The role of traditional medicinal chemistry in the context of these efforts is considered. Every practicing medicinal chemist labors under an assumption that is almost never stated out loud, not all potentially useful drugs for human use have yet been found. It certainly seems like a reasonable viewpoint, given the number of medical conditions either for which there is no pharmacotherapy available or for which existing treatments leave much to be desired. However, another way of addressing this need has gained steam in recent years. “Drug repurposing” is the practice of looking for new clinical uses of existing drugs, which contrasts sharply from de novo drug discovery approaches to therapeutics. The purpose of this essay will be to consider this approach, contrast it to traditional medicinal chemistry, and consider how the two approaches could positively complement each other.

 

KEYWORDS: Drug repositioning, drug discovery, cost effective, recycling, re-tasking.

 

 


INTRODUCTION:

Drug development process is long (10-15 years) and it is expensive. It is relatively new field in pharmacology, that it is focused on discoveries of new indications. Drug companies are seeking new approaches to bring new drugs to market. One approach to drug discovery is that of drug repositioning which focuses on identifying novel uses for existing drugs. Finding a new use for an existing compound hold many appeals. Typically the safety, efficacy, and toxicity of an existing drug have been extensively studied, and therefore data have already been accumulated toward gaining approval by the U.S. Food and drug administration (FDA) for a specific indication.

 

The primary concern of all who engage in applied biomedical research should be helping patients in the absence of disciplinary bias. For the medicinal chemist, this means that the goal is to identify the best drug regardless of provenance or commercial concerns (including the recognition that drug therapy itself is not always the best course of action). Of course, pragmatic compromises must usually be considered, whether scientific or economic in nature. “Best” has a temporal connotation as well: the “best” drug today can change as new agents are introduced or as new information is obtained in and beyond clinical trials. For example, there are numerous conditions for which patients would gladly accept an imperfect cure, especially if one does not presently exist. In such cases, the lives of those who suffer improve to some degree, immediately. The state-of-the-art therapies in such areas as Alzheimer’s or Parkinson’s disease, as well as many types of cancer, can very much be viewed in this way. Attaining such a status quo does not mean that all research toward better treatments will stop. To the contrary, this is one area where the self-correcting nature of science flowers best, as scientists and clinicians work together to build a better tomorrow on top of yesterday’s achievements.

 

One of the hardest parts of a de novo drug discovery campaign is starting out, in part due to the challenges of selecting and establishing initial structure–activity relationships on a given chemical series to explore. The short-term assessment of chemical series may be relatively easy to uncover through the selection of appropriate assays and biological models selection, but selecting the right series—i.e., one able to surmount all of the hurdles between discovery chemistry and the clinic—is much harder for the no clairvoyant. Conventional wisdom has deemed most of the innovations meant to increase passage from early- to late-stage drug discovery wanting, especially the coupling of combinatorial chemistry with high-throughput screening.1

 

Although the idea that combinatorial chemistry or any other individual approach has failed is debatable, one thing that everyone can agree on is that it is harder than ever to develop a new drug and that these challenges have negatively impacted the global pharmaceutical enterprise.

 

BASICS OF DRUG REPURPOSING:

Drug repurposing is the process of finding a new medical indication for a drug. The drug might be currently approved for another use, withdrawn because of adverse effects, or not accepted for failing to prove efficacy. Although many cases of drug repurposing emerged from serendipity by discovering beneficial side effects of drugs for patients in a regime, numerous efforts are arising to perform drug repurposing deliberately with more systematic approaches. Known facts that make drug repurposing possible are the poly pharmacology of small molecules (that allows a drug to have an activity on more than one target) and the connections among metabolic pathways (so that changes in the activity in a given target can affect indirectly the overall activity of other targets).

 

Poly pharmacology of small molecules can not only cause adverse effects but also lead to drug repurposing. Size, polarity, and concentration are major features upon which a drug’s promiscuity depends. Poly pharmacology can be largely exploited, since a drug hits on average six to 13 targets. Nonetheless, very promiscuous drugs may have a considerable number of undesired effects. Therefore, many strategies to predict poly pharmacology have been developed. Also, metabolic pathways can be exploited to repurpose drugs given that many diseases involve multiple genes, whose products may be involved in multiple pathways.

Other, nonscience-based factors have been partly responsible for the uptick in drug repurposing efforts, especially in academic- or foundation-based drug discovery efforts, many of which do not have at their beck and call a team of highly skilled medicinal chemists. For universities and research institutes seeking to establish themselves as bonafide players in drug discovery, a significant milestone is entry of a compound into clinical trials. The attractiveness of the repurposing approach for that milestone is obvious, even if the validity of entry into clinical trials as the primary measure of success (as opposed to successful passage through clinical trials into the clinic) is subject for discussion. Moreover, when confronted with the recognized difficulties and crushing expense of bringing a molecule all the way from discovery/design/optimization and into the clinic, the allure of a repurposing approach is understandable.

 

What does all of this say about the role of the medicinal chemist in the twenty-first century? Some are quick to point out the downsides of repurposing, ranging from the lack of understanding of how the molecules are working (i.e., when the repurposed drug arose from a phenotypic or alternative assay lacking resolution vis-à-vis target) to the challenges of formulating a workable business model for patenting and employing a treatment that someone already owns. However, to defend traditional drug discovery by pointing to these concerns would be a cop-out. If real cures are to be found through drug repurposing of any ilk, creative solutions to its problems will not be far behind. And we owe it to patients to provide help regardless from which scientific approach the help arises or who benefits. (Remember that stuff about “identifying the best drug regardless of provenance”? I meant it.)

 

It is always dangerous to make predictions and doubly so to do it in print, but here goes. I suspect that drug repurposing, from a strictly scientific perspective, will grow in popularity as its potential is demonstrated and successes are seen. But like combinatorial chemistry and nearly every other “new” technology or approach, it is likely to reach a point where limits become more and more clear. At this point, discovery tools tend to reach their appropriate equilibrium and become accepted, warts and all, for what they are. Unless, in the process, it becomes clear that every useful drug molecule has indeed already been discovered (which is so unlikely, given the vastness of chemical space and the diversity of both target- and non-target based challenges in negotiating the biological milieu), de novo and repurposing approaches to drug therapy discovery will coexist.

 

 

 

While giving drug repurposing its chance to succeed or fail on its own merits, I’d like to advocate for maintaining a strong pipeline of drugs discovered and developed through de novo medicinal chemistry. This is due to the unique ability of synthetic medicinal chemistry to provide and optimize novel chemical matter and my strong sense that the need for such compounds is not going to end anytime soon. Drug repurposing’s or, especially, drug rescue’s reliance on finding a molecule in just the right chemical spot to cross the goal line is analogous to scoring in American football via pass interception or fumble recovery near the goal line. It is great when it happens, but successful football teams need a diversified strategy that also includes the long game, as tough as it can be. To this point, a case can be made that the additional time needed to optimize a given agent through SAR may not be the overwhelming cost driver in current drug development when compared to the cost of clinical studies.

 

ENTERING DRUG REPURPOSING:

Generically, drug repurposing is a collection of approaches that collectively seek to adapt the current pharmacopeia for new uses.2−4Included in the complicated taxonomy that is being developed for such approaches5 is “drug rescue”, in which promising compounds that have been developed for one indication but have failed to reach the clinic are redirected toward another. For the purposes of this discussion, I will not attempt to differentiate between different flavors of drug repurposing but consider the concept in broad strokes.

 

The proponents of drug repurposing cite numerous scientific advantages of the idea. To my mind, foremost among these is related to a prime challenge in moving a molecule discovered by target-centric biology forward, namely establishing the validity of a new biological target in the treatment of disease. In this view, a considerable amount of time may be saved, as clinical trials would have been facilitated by the fact that the fictional repurposed candidate would have already been approved for use in humans. Other advantages attributed to repurposed drugs accrue from the fact that so much is known about them relative to newly synthesized molecules. As a class, they have at least tolerable safety and pharmacokinetic profiles, or they would not have been approved in the first place; minimally, one knows what one is dealing with (although it must be noted that, for drug rescue programs, one also knows that one is dealing with drug candidates that have, in fact, failed to reach the clinic). There are no hidden issues with respect to manufacturing or stability issues, and indeed, many drugs are off patent and may provide relatively inexpensive solutions for new problems. And they are available. Pragmatically, one can dovetail a repurposing effort with screening by the modest expedient of replacing a traditional screening library, which often contains hundreds of thousands of compounds, with a much smaller library of approved drug candidates. Such a library is a key component of one important approach to drug repurposing/rescue being carried out under the banner of the newly formed National Center for Advancing Translational Science6−9. Careful combinatorialization of the screening effort might uncover novel combinations of agents that are superior to single compounds, an approach that would be harder to apply to larger numbers of relatively unknown compound streams that would still require optimization (as might the repurposed drugs as well, but more about that shortly).

 

CHALLENGES AND OPPURTUNITIES:

Drug repositioning is an innovation stream of pharmaceutical development that offers advantages for drug developers along with safer medicines for patients. Several drugs have been successfully repositioned to a new indication, with the most prominent of them being viagra and thalidomide, which have generated historically high revenues. In line with these developments, most of the recent articles and reviews on repositioning are focused on success stories, leaving behind the challenges that repositioned compounds have on the way to the clinic. Here, I analyze repositioning as a business opportunity for pharmaceutical companies, weighing both challenges and opportunities of repositioning. In addition, I suggest extended profiling as a lower-risk cost-effective repositioning model for pharmaceutical companies and elucidate the novel collaborative business opportunities that help to realize repositioning of shelved and marketed compounds.

 

The FDA, drug patents, and generic drug approval:

Generic drug approvals in the US are subject to a detailed regulatory scheme set up by the Hatch-Waxman Act in 1984. Applicants seeking approval of a generic drug typically do so with an Abbreviated New Drug Application, or ANDA. The primary scientific data required in an ANDA is the demonstration that the generic product is bioequivalent to the originally-approved drug. Expensive clinical trials are not required, because ANDAs rely on the safety and efficacy data generated under the original New Drug Application, or NDA, of the original innovator. However, if the original drug product or its use is covered by patent listed in the FDA’s Orange Book, generic marketing approval is effective only after the patents expire. The exception is when the ANDA-filer certifies that the relevant patents are invalid or not infringed. Such certification opens the generic drug company to patent litigation, and an automatic 30-month stay of ANDA approval when the patent infringement suit is filed. Thus, having Orange Book-listable patents is a major consideration when investing in drug development.

 

Table 1: Drugs that have been successfully repositioned

DRUG

ORIGINAL INDICATIN

NEW INDICATIN

Amphotericin B

Fungal Infections

Leishmaniasis

Aspirin

Inflammation, Pain

Antiplatelet

Bromocriptine

Pakinson’s disease

Diabetes mellitus

Finasteride

Prostate hyperplasia

Hair loss

Gemcitabine

Viral Infectin

Cancer

Methotrexate

Cancer

Psoriasis, rheumatoid arthritis

Minoxidil

Hypedrtension

Hair loss

Raloxifene

Cancer

Osteoporosis

Thalidomide

Morning sickness

Leprosy, multiple myeloma

Sildenafil

Angina

Erectile dysfunction, pulmonary hyprtension

 

FUTURE OF DRUG REPOSITIONING:

Drug repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs. In order to circumvent some of the most expensive drug discovery processes, companies pursue this strategy to increase their productivity (new drugs to market) by reducing the discovery and development timeline. This decreases the overall cost of bringing the drug to market because the safety and pharmacokinetic profiles of the repositioned candidates are already established. The term “drug repositioning” has been used interchangeably with “drug repurposing” or “drug reprofiling.” All these expressions are relatively synonymous for describing the process that seeks to discover new applications for an existing drug that were not previously referenced and not currently prescribed or investigated.

 

This review will summarize novel methods being used to accelerate the discovery of old drugs that could potentially treat new indications, either via the established mechanism of action or by identification of new ones. Representative case studies of these approaches to therapeutics discovery will also be highlighted. Researchers have previously identified repositioned drugs by serendipity, novel insights, or target searching.

 

COMPUTER AIDED DRUG REPURPOSING:

Drug repurposing is an attractive approach to speed up drug discovery and reduce the large costs associated with the drug discovery process. Of note, the large cost of drug development will impact directly the budget of the patients and may represent a significant burden in the access of the drug to the patient. Drug repurposing has led to several successful stories of drugs that are being employed for an indication different from the original, including novel applications in oncology. Repositioning a drug can be conveniently achieved using a blend of experimental and computational strategies. Computational strategies are playing a key role to uncover epigenetic modulators among drugs currently targeted for other indications. For example, for DNMTs, similarity-based virtual screening led to the identification of the anti-inflammatory drug olsalazine as a distinct hypomethylating compound. In a follow-up study, olsalazine is being used as query to identify novel hypomethylating agents in databases of approved drugs. A second recent example of a drug repurposing project guided by computational approaches is the identification of the antiviral drug ribavirin as inhibitor of histone Methyl Transferase zeste homolog 2 (EZH2). Ribavirin is a Guanosine analog that is used to stop viral RNA synthesis and viral mRNA capping. Ribavirin is a known inhibitor of eIF4E and Inosine 5′-phosphate dehydrogenase and also inhibits histone Methyl Transferase zeste homolog 2, EZH2.

 

Similarity searching revealed that ribavirin has a high structural similarity to 3-deazaneplanocin A, a known inhibitor of EZH2. In that work, the growth inhibitory effects of ribavirin as well as its effects upon epigenetic enzymes were evaluated in various cancer cell lines. It was found that ribavirin decreased EZH2 expression, inhibited histone Methyl Transferase activity, and decreased H3K27 trimethylation (De la Cruz-Hernandez et al., 2015). It is expected that more systematic, computer-guided drug repurposing campaigns will be conducted not only for DNMT or histone Methyl Transferase but also for other epigenetic targets.

 

DISCUSSION:

As long as the field has existed, medicinal chemistry has sought to incorporate new tools and approaches to accomplish its mission of providing society with new and better drugs. Drug resourcing need not deter us from this path, even if it means that the mission statement will sometimes be edited to read “providing society with better drugs that are not necessarily so new”. So long as the field of medicinal chemistry continues to demonstrate its worth by providing novel solutions to important problems, and so long as these efforts are supported by the business and academic research communities, we will earn our place in the global biomedical research community.

 

CONCLUSION:

To provide information about the repurposing existing drugs for new indications and therapeutic innovation and difference between original and new indications and it also makes particular sense for patients. With a repurposed drug, the safety profile is much better understood than for an entirely new medicine. Repurposing a known drug is therefore safer for patients than use of a new drug with little or no track record.

 

REFERENCES:

1.        Kennedy J. P.et al., “Application of Combinatorial Chemistry Science on Modern Drug Discovery”, J. Comb. Chem. 2008, 10, 345–354.

2.        Ashburn T. et al.,” Drug Repositioning: Identifying and Developing New Uses for Existing Drug”,. Nat. Rev. Drug Discov. 2004, 3. 673–683.

3.        O’Connor K. A. et al.,” Finding New Tricks for Old Drugs: An Efficient Route for Public-Sector Drug Discovery”, Nat. Rev. Drug Discov. 2005, 4, 1005–1014.

4.        Oprea T. I.et al.,” Drug Repurposing from an Academic Perspective”, Drug Discov. Today: Ther. Strategies 2011, 8, 61–69.

5.        Doan T. L.et al.,” The Future of Drug Repositioning: Old Drugs, New Opportunities”, In Annu. Rep. Med. Chem.., Macor J. E., editor., Ed. Academic Press: Oxford, 2011, Vol. 46, 385–401.

6.        Huang R.et al.,” The NCGC Pharmaceutical Collection: A Comprehensive Resource of Clinically Approved Drugs Enabling Repurposing and Chemical Genomics”, Science Translational Med. 2011, 3, 80, 1-16.

7.        Collins F. S.et al.,” Mining for therapeutic gold”, Nat. Rev. Drug Discov. 2011, 10, 397–397.

8.        The Discovering New Therapeutic Uses for Existing Molecules initiative was announced by NIH on May 3, 2012.

9.        http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/therapeutic-uses.html

 

 

 

Received on 10.05.2019         Accepted on 01.06.2019

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2019; 9(4):268-272.

DOI: 10.5958/2231-5691.2019.00044.3