Current Medicinal Chemistry - Volume 20, Issue 13, 2013

In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuse argument that is spurring the development of multitarget therapies.

The history of Fixed Dose Combination (FDC) oral drug products has been tumultuous over its history. Some FDCs were prepared for marketing purposes and others for clinical improvements. Often, the products prepared for marketing advantage ended up causing negative outcomes. However, in recent years, there has been a resurgence of FDCs as clinicians have found them adventitious for treatment of AIDS/HIV and for oral contraceptives, just to name two examples. International regulatory Agencies and most major drug regulatory agencies have established guidelines along with regulations concerning preparation, labeling and marketing for FDCs. The advantages of FDCs are said to be in the clinical realm where simplified therapy regimens are thought to enhance patient's medication taking compliance. On the financial side, health insurers and other payers normally save money from a decreased number of dispensing fees, the use of fewer bottles, labels, etc., and from the possible situation where the price of the FDC is less than the medication price of the two separate ingredients dispensed individually. Overall, there is a great deal of evidence in favor of appropriate FDCs.

Polypharmacology offers a model for the way drug discovery must evolve to develop therapies most suited to treating currently incurable diseases. It is driven by a worldwide demand for safer, more effective, and affordable medicines against the most complex diseases, and by the failures of modern drug discovery to provide these. Polypharmacology can involve combinations and/or multitarget drugs (MTD). Although not mutually exclusive, my premise is that MTDs have inherent advantages over combinations. This review article focuses on MTDs from a medicinal chemistry perspective. I will explore their use in current clinical practice, their likely application in the future, and the challenges to be overcome to achieve this goal.

Prediction of polypharmacology of known drugs and new molecules against selected multiple targets is highly useful for finding new therapeutic applications of existing drugs (drug repositioning) and for discovering multi-target drugs with improved therapeutic efficacies by collective regulations of primary therapeutic targets, compensatory signalling and drug resistance mechanisms. In this review, we describe recent progresses in exploration of in-silico methods for predicting polypharmacology of known drugs and new molecules by means of structure-based (molecular docking, binding- site structural similarity, receptor-based pharmacophore searching), expression-based (expression profile/signature similarity disease-drug and drug-drug networks), ligand-based (similarity searching, side-effect similarity, QSAR, machine learning), and fragment-based approaches that have shown promising potential in facilitating drug repositioning and the discovery of multi-target drugs.

Neurodegenerative diseases are complex disorders with several pathoetiological pathways leading to cell death. Rationally designed multi-targeted agents, or “multi-targeted designed drugs” (MTDD) show significant promise in preclinical studies as neuroprotective and disease-modifying agents. In this review, we highlight the use of chemical scaffolds that lend themselves exquisitely to the development of MTDDs in neurodegeneration. Notably, synthetic polycyclic cage compounds have served as scaffolds for novel voltage-gated calcium channel blockers, NMDA receptor antagonists, and sigma-receptor ligands – attractive targets in neurodegeneration. In an entirely different approach, compounds containing the thiazolidinedione moiety (referred to as glitazones) alter mitochondrial function through the mitochondrial protein mitoNEET, an attractive new drug target for the treatment of neurodegenerative diseases. The design strategy for yet another agent, ladostigil, employed the amalgamation of active chemical moieties of the AChE inhibitor rivastigmine, and the monoamine oxidase-B (MAO-B) inhibitor rasagiline, leading to a single compound that targets both enzymes simultaneously. Natural products have also served as design templates for several MTDD design studies. In particular, the stilbene scaffold has become popular in particular due to the neuroprotective effects of the non-flavonoid natural product resveratrol. Recently, stilbene scaffold-based compounds were developed to reduce - through chelation with metal ions that interact with beta-amyloid - both metal-induced beta-amyloid protein aggregation, and ROS generated from this aggregate. Other subtle modifications of the stilbene motif led to the creation of reversible, non-competitive MAO inhibitors. Finally, compounds derived from the xanthine scaffold afford neuroprotection in Parkinson’s disease through mechanisms that include dual adenosine A2A receptor antagonism and MAO-B inhibition.

Modern medicinal chemistry has come to its bottleneck and is full of challenges, specially when facing with long-term central nervous system (CNS) disorders induced by several factors, such as Alzheimer's disease (AD) or Parkinson's disease (PD). In order to probe these challenges, multi-target directed ligands (MTDLs) design has been applied recently by medicinal scientists trying to get single compounds that can simultaneously modulate multiple targets. In addition, natural products have drawn the attention of drug developers again in recent years, as they have been used by human race for thousands of years and are full of diversity with their concomitant high potential to exhibit biological activities. We hereby review some of the research within the last few years focusing on multiple-target compounds acting in the CNS using natural products as lead resources. The target compounds obtained and described here represent bioactive hybrids either covalently connected or obtained by fusion of different bioactive moieties with at least one part derived from or representing directly natural products, along with some natural compounds themselves showing multiple pharmacological activities. We describe suitable ways to connect the drug components chemically, how to use the approach to enhance biological activity and selectivity, as well as potential drawbacks of the hybrid approach. This review will also show the rationale that these MTDLs are more than just the sum of their components but in many cases should be considered as new pharmacological entities in their own respect.

The etiopathology of Alzheimer's disease (AD) is extremely complex and heterogeneous, often associated with comorbidities. As a result it may be unlikely that AD may be mitigated by drug acting on a single specific target. The current tendency in drug design and discovery in AD is the rational design or “serendipitous” discovery of new drug entities challenging multiple targets. Since two of the presently approved drugs for AD are based on natural products (galantamine and the physostigmine-derivative rivastigmine), many plants are now under investigation as a potential source of new drugs. Multifunctional drugs often have their origin in natural sources. This review is limited to plant chemicals having different targets with actual (galantamine) or promising (drugs from Crocus sativus, Ginkgo biloba, Salvia species, and Huperzia serrata) clinical evidence in people with dementia or AD.

Balanced modulation of multiple targets is an attractive therapeutic strategy in treating complex diseases including cancer. Comparing with drugs combination, single molecule modulating desirable multiple targets has advantages in pharmacokinetic and pharmacodynamics. Different from previous reviews, we provided an overview of reported multitarget antitumor agents from the viewpoint of pharmacophores. These multitarget antitumor agents were designed by combination of pharmacophores or by high-throughput screening plus structural modification, which were exemplified by the privileged pharmacophore quinazoline and several other popular pharmacophores, including phenylaminopyrimidine, anthracycline and naphthalimide. Previous research demonstrated the importance of in-depth validation against multiple targets not only in cell-free system, but also in cancer cells. Furthermore, the multitarget compounds were also effective for resistance cell lines which highlighted their antitumor potency in the era of increasing drug resistance in cancer patients.

Protozoan infections are the leading cause of morbidity and mortality among parasitic infections of humans, accounting for approximately 800 thousand mortalities and a loss of more than 30 million disability-adjusted life years annually. The major protozoan infections of humans, namely malaria, Chagas disease, human African trypanosomiasis, and leishmaniasis, are primarily centered in the tropics, with a reach into some subtropical regions of the world. Though globally massive in their impact, these diseases mostly afflict the least economically endowed and geographically marginalized populations in low-income countries. As such, there is no sufficient market incentive for industrial businessdriven antiprotozoal drug discovery due to poor marketing prospects and low returns on investment. Consequently, the pharmacopoeia for majority of these diseases, composed mainly of agents with poor efficacy and unsatisfactory safety profiles, has essentially remained unchanged for decades, creating a compelling need for more efficacious and better tolerated medicines. The policy makers and the scientific community are seeking effective ways to meet this need. So far, two approaches have emerged promising in this regard: combination chemotherapy and drug repositioning. Molecular hybridization has been cited as a potential third approach that could be used to deliver new antiprotozoal chemical entities. In this review article, recent applications of this novel strategy in antimalarial, antichagasic, antitrypanosomal, and antileishmanial drug discovery research and development over the last five years will be presented and discussed.

Multitarget-directed ligands (MTDLs), an emerging and appealing drug discovery strategy, utilizing a single chemical entity to inhibit multitargets, was confirmed to be effective in reducing the likelihood of drug resistance, diminishing problems of dosing complexity, drug-drug interactions and toxicities, as well as improving patient compliance. The exploration of MTDL strategy should be valuable in anti-HIV drug discovery. In this article, current knowledge and strategies for the rational design of the multitarget and selective anti-HIV agents are described and a number of illustrative examples are given. Moreover, the challenges, limitations and outlook of such novel drug design strategies are also presented, with a goal to highlight the representative paradigms in the rational design of MTDLs, and to help medicinal chemists discover the next generation of multitarget anti-HIV agents.

Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called “privileged structures”. Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.

Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.