Supramolecular Chemistry in Drug Discovery

Contributing writer Lily Bryant

Supramolecular chemistry has important medical applications, as it aids the development of new drug therapies by helping researchers to understand how medications interact at the target binding sites in the body. This area of chemistry has also aided the development of binding drugs that are able to alter the target substance and its properties, so the substrate is unable to reach its action site or trigger the usual biological response. Examples of this are the phosphate binding drug sevelamer hydrochloride, which is used to manage raised phosphate levels in advanced cases of chronic kidney disease, and the selective binding agent sugammadex, which reverses neuromuscular block brought on by vecuronium and rocuronium during anesthesia. However, supramolecular chemistry is also important for the development of drug delivery systems, which offer encapsulation and targeted release.

Peptoid nanosheets

Researchers from Lawrence Berkeley National Laboratory have recently made a development that will hopefully pave the way to more effective and safer drug delivery systems. These systems can help to reduce the unwanted side-effects associated drug therapies, which are sometimes severe enough to discourage patients from accepting medication or mean that they have to abandon treatment. As with opiate based painkillers, the untargeted nature of their actions means that some drugs may even lead to addiction. While intrathecal delivery of painkillers can help those people struggling with chronic pain that is difficult to control, it isn’t without its risks and more precise targeting of drugs with the aid of molecular delivery systems could offer more successful results without the adverse effects.

The team which previously developed peptoid nanosheets that come together where air and water meet have now created peptoid nanosheets that come together where oil and water meet. If you are not familiar with the concept of a peptoid nanosheet, this is a synthetic 2D protein structure, which typically has a thickness of just three nanometers, making it one of the thinnest organic 2D crystalline materials available. Just like natural proteins, peptoids are able to fold and curve into specific shapes, enabling them to complete precise functions. As it is possible to customize the peptoids from which they are formed, this makes the properties of these nanosheets flexible, meaning that they are a good candidate in the area of drug delivery. Additionally, the very large surface area of peptoid nanosheets makes them ideal for sensing and recognition, which is again vital for drug delivery. Another useful property for these applications is their hydrophobic core, which excludes water molecules, meaning that peptoid nanosheets have the potential to carry hydrophobic cargos, as demonstrated by research published in ACS Nano. Finally, peptoids are not as sensitive to chemical or metabolic changes as proteins, so they are less likely than natural proteins to break down, which is advantageous when using them within the body.

The latest findings, which were published in the September edition of the Proceedings of theNational Academy of Sciences USA, show how it is possible for these specific and highly organized peptoid sheets to form at a water-oil interface. Spectroscopic measurements confirm that the monolayers are extremely well ordered and that it is the electrostatic action between charged molecules on the peptoid that allow the formation of this orderly structure at the surface of oil and water. The ability to create these nanosheets using oil instead of air creates new possibilities for their production6. It would also allow the development of libraries of various functionalized nanosheets and allow screening for peptoid nanosheets that have the same molecular recognition as specific proteins, which would aid future drug discoveries. While the production of peptoid nanosheets with drugs in their interior is still some way off, these findings open up the possibility of extending the complexity and functions of 2D nanomaterials, which can only aid the development of drug delivery systems.

About Lily Bryant

Lily Bryant is a writer working with one of only two licensed online pharmacies in the US. She is strongly interested in promoting and creating content aimed at relevant readers as part of her role in ethical healthcare business. She believes that it is important that we play a strong role in leading society towards a healthier lifestyle through the promotion of exercise and healthy diet rather than an early adoption of drug treatment.

Hope for Drug to Reduce Old-Age-Related Muscle Wasting

Guest Post – Lily Bryant

The results of a study carried out by researchers at the Center of Regenerative Medicine at Massachusetts General Hospital in Boston, USA, and the Department of Craniofacial Development and Stem Cell Biology at King’s College London, England, indicate that a cure for muscle weakening caused by old age might be on the horizon. Muscle wasting is an inevitable symptom of growing older. It can be slowed down by regularly exercising but there is no known way of reversing it at the moment. This looks set to change though, as the researchers have treated old mice with a drug that has significantly improved the ability of their aged muscle tissue to self-repair. 

Fibroblast Growth Factor 2 

Strenuous activity, such as doing press-ups or lifting weights, results in a small level of damage to the muscles. Stem cells are triggered to repair them by dividing and developing into new muscle fibers. This results in big arms and rippling torsos. However, weakening of the muscles due to old age means that bulging biceps can soon become puny and weak. This occurs because as people grow older, their muscle loses its ability to regenerate. A study conducted by the University of Potsdam in Germany indicates that people lose just under a third of their muscle strength between the ages of fifty and seventy. The researchers at Massachusetts General Hospital and King’s College London deduced that this is due to the fact that the number of dormant stem cells in muscles decreases with age. They concluded that in mice, this was caused by excessively high levels of a protein that stimulates cells to divide, known as fibroblast growth factor 2 (FGF2). 

Preventing Muscle Stem Cell Decline 

In aging muscle, fibroblast growth factor 2 was found to be continuously awakening dormant stem cells for no reason. The stem cell supply was observed to deplete over time, meaning that an insufficient number were available when they were really needed. As a result of this, muscle regeneration ability was impaired. The researchers discovered that using a drug called SU5402 that inhibits fibroblast growth factor 2 can prevent muscle stem cell decline in aging mice. Treating the elderly rodents with this drug increased their ability to repair muscle tissue. 

Reducing the Impact of Old Age 

Dr Albert Basson, who is a senior researcher at King’s College London, has stated that the findings mean that treatments that could make old muscles young again could one day be developed, thus reducing the impact of old age. He says that if such a treatment came into existence, people would be able to live more independent, mobile lives as they grew older. Senior author Dr Andrew Brack of Massachusetts General Hospital says that just as it is important for athletes to schedule recovery into the time that is taken for training, stem cells require time in which to recuperate but elderly cells recuperate less often. Scientists are yet to figure out why it is that levels of fibroblast growth factor 2 increase causing excessive stem cell activation as people get older. Research team member Kieran Jones of King’s College London says that the next step is to conduct an analysis of old muscle in humans in order to see whether or not the same mechanism is responsible for the depletion of stem cells in human muscle fibers leading to wasting and loss of mass. 

The Implications of the Research 

Once it has been confirmed that stem cells in human muscle fibers are negatively affected by fibroblast growth factor 2, work can start on introducing a drug to the market that will stop the process from taking place and consequently reduce the extent to which elderly people are immobilized and prevented from doing what they want to do by the effects of age-related muscle weakening. The average life expectancy in India has increased by over four and a half years since 1998. Now that people are living longer than they used to live for, a drug that reduces the amount to which becoming elderly negatively impacts upon the quality people’s lives would be extremely beneficial. It would mean that individuals who have reached the later stages of their lives could enjoy the time that they have left without having their independence limited by their muscles becoming increasingly weak and feeble.

About Lily Bryant

Lily Bryant is a writer working with one of only two licensed online pharmacies in the US. She is strongly interested in promoting and creating content aimed at relevant readers as part of her role in ethical healthcare business. She believes that it is important that we play a strong role in leading society towards a healthier lifestyle through the promotion of exercise and healthy diet rather than an early adoption of drug treatment.

Harmless Viruses Might be a Potential Treatment for Acne

Guest Post – Lily Bryant

According to a report published in the Indian Journal of Dermatology, Venereology and Leprology, there are thought to be between two million and three million acne sufferers in India. Acne can lead to low self-esteem and image problems and is the scourge of teenage boys all over the country. Fortunately towards the end of 2012, researchers at the University of California, Los Angeles, and the University of Pittsburgh in the United States discovered that phages living on our skin possess the ability to kill propionibacterium acnes, which is the virus that causes it. This could be good news for those whose skin is tarnished by this condition and mean that an end is in sight.

There has been a rapid increase in the promotion of drugs aimed at enhancing individuals’ physical appearances in recent years. The weight loss industry has grown at a yearly rate of over twenty-five percent, with more people than ever purchasing diet pills and fat burners, the hair loss treatment industry has been growing by one percent per year and the acne treatment industry has also seen significant growth. People’s daily lives are affected in a major way by how they look so a cure for acne could be both highly profitable for the pharmaceutical company that is responsible for it and highly beneficial to sufferers.

Immune Resistance Unlikely to Develop

In order to arrive at their discovery, the researchers at the two universities analysed phages and deduced that they make endolysin, which breaks down propionibacterium acnes before killing it. They also discovered that the phages shared eighty-five percent of their DNA. This is unusual for viruses and means that when used as a treatment, it would be unlikely that immune resistance would develop.

Advantages Over Other Forms of Treatment

Unlike antibiotics, which kill many different types of bacteria including ones that live in the gut and can have positive effects, phages are programmed to only target specific bacteria. According to director of the University of California, Los Angeles, Clinic for Acne, Rosacea and Aesthetics Dr Jenny Kim, who was one of the researchers, many acne strains are now resistant to antibiotics such as tetracycline, as they are so widely used. Drugs like Accutane are still effective but can have risky side effects, which limits their use. The researchers at the two universities have stated that phages could offer a tailored therapy that has less adverse side effects. Therefore phages could be the new form of acne medication that those inflicted with the condition have been looking for.

Development of New Drugs and Treatments 

Study co-author Graham Hatfull, who is a biotechnology professor at the University of Pittsburgh, has stated that there are two ways in which this research could be used with regards to the development of new drugs and treatments. He says that phages could either be used directly as therapy for acne or phage-based components could be utilized. Professor Hatfull also says that the work that the University of California, Los Angeles, and the University of Pittsburgh have carried out has provided the world with useful information about phages and paved the way for the thinking up of potential applications for them. He points out that whilst acne is a condition that a significant percentage of the population is likely to suffer from at some point in their lives, there are still currently few effective methods for curing it. Hatfull says that harnessing a virus that naturally preys upon the bacteria that causes spots looks to be a promising means of reducing both the physical and the mental scars that acne can inflict upon individuals.

Implications of the Research

It appears that being forced to endure pimples and spots could soon bee a thing of the past. The results of a study published in the Journal of Cosmetic Dermatology in 2010 demonstrate that acne can severely negatively impact upon the self-esteem of sufferers and increase the risk of them developing psychological disorders. It can make them two to three times more likely to become clinically depressed. Therefore it is high time that there was a means of treating it and phages could provide the answer. Now it is just a matter of deciding what the best way of using them to gain the optimum results in acne reduction is.

About Lily Bryant

Lily Bryant is a writer working with one of only two licensed online pharmacies in the US. She is strongly interested in promoting and creating content aimed at relevant readers as part of her role in ethical healthcare business. She believes that it is important that we play a strong role in leading society towards a healthier lifestyle through the promotion of exercise and healthy diet rather than an early adoption of drug treatment.

Modulators of Protein–Protein Interactions

Protein-protein interactions (PPI) play a crucial role in most biological processes. This nature of PPI has put forward itself as a prospective candidate for therapeutic intervention. Traditional small molecule target classes such as Enzymes, GPCRs, Kinases, etc. have a deep pocket (often used to bind an endogenous substrate), where small molecules tend to bind. On the other hand, PPIs appear to be too large and featureless for small molecules to bind against. Hence, due to this lack of well-defined binding pockets, they were considered unsuitable/ extremely hard for targeting small molecules. 

Attempts at generating small molecule modulators of PPIs have been largely unsuccessful by adopting existing chemical techniques. This leads us to believe that we need to identify novel chemical space that can leverage the flat and expansive surfaces of PPI, which would in turn provide an effective binding for small molecules. However, pharmaceutical companies are rather unwilling to add compounds containing multiple rings, multiple stereocenters that are highly complex, into their corporate collection as it does not align with their immediate short-term business goals.

Heterocyclic compounds (aromatic, largely flat and hydrophobic)

+

Natural products (rich in sp2 bonds)

=

Natural Product Inspired   (New Chemical toolbox)

Dr. Prabhat Arya is developing a new chemical toolbox enriched with both Heterocyclic Compounds and Natural Products to tackle such issues from Dr. Reddy’s Institute of Life Sciences. This approach could create a large 3D surface area, numerous binding interactions, rich stereochemical diversity, which would, in turn, solve the poor cell permeability of natural products, not to mention the added advantage of overcrowded IP Space.

The field of small-molecule-PP interactions appears to be highly promising, and in the near future, we can hope to see several strategies and techniques that will pave the way towards discovering novel agents in this regard.

Totally drug-resistant TB

One of the biggest problems in Tuberculosis (TB) therapy nowadays is that patients have to take antibiotics for up to 9 months. As many patients feel better before this time, they prematurely stop their treatment, leaving pools of the most drug-resistant M. tuberculosis in their lungs. This contributes to the emergence of complete drug resistance in future patients.

In the past few years, strains of drug-resistant Mtb have become prevalent. In fact, resistance is so widespread that it is now being classified as multi-drug resistant (MDR-TB) and extreme-drug resistant (XDR-TB). Two of the world’s most populous countries, India and China, account for more than 50% of the world’s MDR-TB cases.

Recent reports have also confirmed a new Mtb strain that is completely untreatable and has been designated as Totally drug resistance TB (TDR-TB). Indeed, strains of Mtb have even evolved resistance to all major available anti-TB drugs. India (2012) is the third country in which a total drug-resistant form of TB has emerged, following cases documented in Italy in 2007 and Iran in 2009. There is a need for a more readily available treatment that is effective against both sensitive and drug-resistant strains of M. tuberculosis is evident.

Enoyl reductase: One target, Two major Global Threats

Tuberculosis and Malaria are two major global threats; both account for 5 million deaths annually (mostly in developing countries). Despite the worldwide ravages of Tuberculosis and Malaria, chemotherapeutic regimens against these two diseases have remained largely unchanged. There is an urgent need to develop novel, effective, and affordable drugs to treat both diseases because the resistance has developed or is developing to existing therapy. Scientists around the world are seeking new ways to combat the two opportunistic pathogens.

Mycobacterium tuberculosis and Plasmodium Falciparum are causative agents of tuberculosis and malaria, respectively. Both organisms share enzymatic components of the type II fatty acid biosynthetic pathway (FAS-II). Enoyl acyl carrier protein reductase (ENR) is one of the key type II enzymes, has been repeatedly validated as an effective antimicrobial target (e.g., INH, diazoborines, triclosan, and thiolactomycin).

Triclosan, the ENR inhibitor, showed excellent activity against both organisms. Targeting ENR  with a new class of compounds may yield new drugs against these devastating pathogens.

The Future of Drug Discovery

 The new technologies promise to fill drug development pipelines with small-molecule candidates unfulfilled, so the pharmaceutical industry is currently undergoing rapid changes. They are moving aggressively into large molecule (biologics) drug development.

"Drug space” that is not part of the current drug development includes non-Lipinski NCEs, nanomedicines, nucleic acid-based drugs, etc. will include in the future. One of the major challenges for a medicinal chemist is to find small molecule inhibitors for protein-protein interactions.

Toxicophores Simplified

Toxicophore is a portion of a chemical structure (molecular functionalities) responsible for the toxic properties of a pharmacologically activity compound. Medicinal chemists study toxicophores to predict and replace the potential reactive moieties in the early drug development process to avoid the drug candidate's later-stage failure. A simplified version of the toxicophores is attached here.

Kinase Inhibitors: beyond Oncology

We recently published a paper in Bioorganic and Medicinal Chemistry, targeting Interleukin-2 inducible T-cell kinase (ITK) for treating Asthma. 

Protein kinases are prime targets for anticancer therapies, but achieving specificity for a particular kinase is challenging because of their close structural similarities. This leads to unwanted side effects, and the toxic outcome may also be due to the result of tissue distribution of kinase inhibitors. Imatinib has been highly successful in treating both chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers but is associated with severe cardiotoxicity. Toxicity may be of less concern with oncologic kinases; what about non-cancer indications? Emerging clinical evidence (Nature Drug Discovery) of oral kinase inhibitors other than cancer shows that kinases could effectively inhibit the number of inflammatory pathways.

Almost all the p38MAPK inhibitors having hepatotoxicity issue. For example, SCIO 469 and Arry 797 initially developed for RA but went into the clinic for post operative dental pain; here, the potential toxicity problems will not show up because the drugs are used only for a very short time. Are BMS-582949 and VX 702 still in development? Different companies have spent hundreds of millions on P38 with nothing to show at the end.

Tasocitinib may be the first kinase inhibitor (JAK3) for non-oncology indication and the first oral DMARD for RA in a decade if it successfully completes Phase III clinical trials.

Naked Discovery

Unlike the highest secrecy in closed-door traditional drug discovery by the pool of rigid mindset scientists, the Open Source Drug Discovery (OSSD) Program aims to address the issue by capturing the youngest and brightest minds around the globe to be a part of developing drugs to treat diseases such as drug-resistant TB and malaria, and HIV. Open-source software may have been around for many years, but using an open-source model to speed up drug discovery is a relatively new idea

"Research labs in India are filled more with technicians, as opposed to creative minds. "You really don’t need to have a doctorate in pharmacy to contribute to developing a drug" said Samir Brahmachari, Director General of India’s Council of Scientific and Industrial Research (CSIR), and he believes that the OSDD can be as successful as Linux or a Wikipedia.

Tuberculosis kills at least 3,30,000 Indians annually and 1.7 million people Globally. The incidence of multi- and extensively drug-resistant strains of TB ( MRD- and XRD- TB ) demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics. Recently, Indian scientists have mapped the Mtb tuberculosis genome under the OSDD initiative of CSIR, giving hope of discovering new drugs for TB. This is the first time that the Mtb genome's comprehensive mapping has been accumulated, confirmed, and made available publicly.

This Connect to decode‘S (C2D) finding may contain critical data to unlock previously undiscovered details of TB, resulting in development opportunities for urgently needed new drugs in India and other developing countries.

Retropharmacology: From Drug to lead

Drug discovery is a lengthy, high-risk, and costly endeavor; many strategies are available to accelerate the development process to provide high-quality drug candidates. The diminished interest in Natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry. However, these new technologies promise to fill the drug development pipeline with small-molecule candidates is unfulfilled. Learning from the past with the appropriate strategy for the future is essential to make a significant difference.

Valerian has been used as a medicinal herb science at least the time of ancient Greece and Rome as a sedative, migraine treatment, pain reliever, insomnia, and other disorders as an alternative to benzodiazepine drugs.

Valerenic acid, a significant constituent of common valerian, is a potent modulator of  GABA-A receptors. In order to develop a broader understanding of structural requirements for GABA-A modulatory activity of valerenic acid. Kopp et al. (chem med chem) synthesized several analogs and found that some of the derivatives such as tetrazole (pic) are proved to be the most potent allosteric potentiators of GABA-induced ion currents, and its activity exceeds the activity of valerenic acid and Diazepam.

This reverse pharmacology approach, relates to reversing the routine ‘laboratory-to-clinic’ progress to ‘clinics-to-laboratories’ (inspired by traditional medicine), can offer a smart strategy for new drug candidates.

The rise biopharmaceuticals

The movement of big pharma into biologics  (biopharmaceuticals) understandably has a direct effect on the pharmaceutical landscape. Companies show a diminishing portfolio revenue from small molecule drugs, primarily because of patent expiration on blockbuster drugs (small molecules) and the reallocation of industry resources towards biologics.

Biologics represent one of the most promising frontiers in pharmacotherapy; USFDA approved more biologics in 2009, the figure includes 19 new molecular entities (NMEs) and six novel biologics. In 2008 FDA approved 21 NMEs and three novel biologics. A substantial improvement in biologics approvals in 2009. (fig.1, Nature Medicine, 139, 16, 2010). Moreover, it is expected to take over from small molecule field in the coming years (fig 2, Nature reviews / drug discovery). However, their cost can be substantial, reaching $200,000 or more annually for treatment (Cerezyme), and the large molecules drugs are administered via injection – a less popular option with patients.

Biologics are gradually going to replace the traditional approach to drug design. Students need to understand industries changing needs if they plan on carriers in this area.

Kill the Bugs, Selectively

“Today, we have tuberculosis drugs you have to take for nine months, why can’t we find one that works in three days” - Bill Gates. 

Tuberculosis (TB) is a chronic contagious disease caused by  Mycobacterium tuberculosis (M.tb), one of the leading causes of death worldwide. The WHO estimates about one-third of the world’s population is infected with M.tb, 10% of those infected will progress to active TB disease during their lifetime. The tuberculosis pandemic has been declared a global health emergency as the growing resistance of M.tb to Antibiotics coincides with the spread of risk factors such as HIV/AIDS and diabetes. TB is a complex disease. The current TB drug regimen, a product of scientific advances of the 1960s, requires six to nine months of treatment for active, drug-susceptible TB. Unfortunately, many patients do not or cannot complete this treatment. Poor adherence and prescribing practices have led to the emergence of multi- and extensively drug-resistant strains of TB (MDR-TB and XDR-TB) that increasingly defy current medicines and spread throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics.

 

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome. A team of scientists led by researchers from Weill Cornell Medical College  has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes. These compounds were showing no apparent toxicity to mammalian cells. The oxathiazolone compounds are the first example of an anti-tubercular agent that inhibits protein breakdown. The ability of brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy. These  findings  may lead to drugs that destroy TB in the dormant stage of the lifecycle.

Tamiflu

A new strain of swine flu, an H1N1influenza virus, is spreading around the globe. The WHO has declared the novel H1N1 influenza virus (swine flu - 2009) outbreak a global pandemic - First Phase 6 Influenza pandemic since 1968.

(_)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used to treat both type A and type B human influenza. Currently, it is the most effective drug for the treatment of Influenza. However, the unmet supply of this drug demands urgent solutions. The manufacture of Tamiflu by Roche Company utilizing naturally occurring shikimic acid as the starting material. Getting stable quality of pure shikimic acid may be problematic. 

The Tamiflu supply problem has piqued the attention of academic chemists. Several labs have already reported new methods for making Tamiflu without shikimic acid. However, it is challenging to evaluate academic syntheses from the standpoint of potential as a manufacturing process because they have not been developed for large-scale operation. Considering the amount of Tamiflu required worldwide, there is an urgent demand to improve the production process.

Here is the retrosynthetic analysis for the shortcut synthesis of Tamiflu. This synthesis initiated by oxa-Michael addition of alcohol to acrolin, which was reported by Zhang et al,

Fluorine in Drug Development

The drug development process (fig. 2) is a lengthy, high risk and costly endeavor; many strategies exist to accelerate the target to clinical candidate selection as well as to provide the highest quality of the candidate. Fluorine and its isotope have many role in the different phases of drug development process. The number of fluorine containing drugs are growing rapidly which include the best selling drugs such as Atorvastatin, Prozac, Ciprobay and Pantoprazole (fig.1).

Target identification:

PET is a nuclear medicine imaging tool that allows three-dimensional quantitative determination of the distribution of radioactive with in the human body. The relatively long half-life, high % of β emission, and relatively low positron energy 18 F make it is most favorable for the Positron Emission Tomography (PET) studies. F MR - Fluorine Magnetic Resonance. allows detection of the presence of the target, in vivo, including assessment of the presence of targets, as well as quantification of their spatial and temporal distribution.

F MR - Fluorine Magnetic Resonance. 

PET- Positron Emission Tomography. 

Lead Finding: Once the target is chosen and identified, and the next stage is typically high-throughput screening of large libraries of chemicals for their ability to modulate the target. F M R allows compound screening using cell-based and animal-based assays (whereas HTS is restricted to cell-based assays). Fluorine plays an important role in the physicochemical properties (see lead optimization) of the molecule, so the HTS screening of fluorine-containing libraries will help for the lead finding. 

Lead Optimization: The small and highly electronegative fluorine atom can play a role in medicinal chemistry. Systematic fluorine scan of ligands is a promising strategy in lead optimization. It not only helps to enhance the physicochemical properties but also to strengthen Protein-Ligand binding interaction. This would make the molecule a safer candidate. 

The current strategies for introducing fluorine atoms into molecules are centered to 

1. Improve metabolic stability,

2. Alter physicochemical properties such as pKa and lipophilicity, dipole moment, and even the chemical reactivity and stability of the neighboring functional groups,

3. Enhance the binding efficacy and selectivity in pharmaceuticals, and

4. Bioisosterism. 

Preclinical and Clinical Studies: The suboptimal pharmacokinetics and pharmacodynamic can lead up to 40% of the drug candidate failing to make it to phase 1 trial. PET can allow assessment of parameters such as drug absorption biodistribution, metabolism, delivery, and dose uses in preclinical studies and can help in systematic planning latter phases. The estimation of pharmacological agents to reach their targets is important in drug trials. This can be done by the ADME techniques based on blood or tissue harvesting and subsequent drug and metabolite analysis. This approach is less than perfect because plasma levels of the compound often do not reflect concentrations in a specific tissue because of the presence of physicochemical barriers such as between blood and brain. Proton Emission tomography provides a reliable measure of tissue drug concentration. 

References 

1) Muller. K et al., Science. 317, 2007, 1881. 

2) Reid G. D et al., Drug discovery today. 13, 2008, 473. 

3) Willmann J. K. et al., Nature reviews drug discovery. 7, 2008, 591.

The rule 2-0

Recently, Aronov from Vertex pharmaceuticals proposed a general ‘rule of thumb’ termed the 2-0 rule for kinase likeness to discriminating kinase inhibitors from the nonkinase molecules.

For kinase activity, the molecule should have

1) One or more heteroaromatic nitrogen’s,

2) One or more heteroaromatic NH group,

3) It contains one or more aniline, and 

4) It contains one or more nitriles.

Around 78% of the kinase compound passes the 2-0 rule.

Are Protein Kinases Drug Targets?

Kinases catalyze the transfer of phosphate groups from phosphate-donating molecules (like ATP) to other molecules. They have been intensively investigated as drug targets for many years. Around 20-25% of the druggable genome consists of kinases, and this target accounts for 20-30% of many companies' drug discovery programs.

Several protein kinase inhibitors have been approved by FDA and available in the market which includes Tykerb®, Sprycel®, Sutent®, Nexavar®, Tarceva®, Iressa®, and Gleevec®. Many other kinase inhibitors are currently undergoing clinical development. This accelerated the research and development in this area, reflecting the number of search results for 'kinase inhibitors'. Sci-finder keyword search resulted in 1281 patents, which is filed in 2007 alone. Drug and Market Development’s (D&MD) report (2005) shows that kinase targeted therapies growing from $12.7 billion in 2005 to $58.6 billion in 2010. 

 

So what is the problem with kinases? The lack of selectivity for targeting a specific kinase is the issue due to the similarity of other kinase targets. For example, the natural product substrate Staurosporine hits almost every kinase out there will be gratuitously toxic. However, the real problem with kinase inhibitors is the toxic outcomes may result from tissue distribution of orally administered kinase inhibitors.

 

Kinases are drug targets. But, difficult ones.

N-Methylation and Oral Bioavailability.

Inspired by the excellent pharmacokinetic profile of transplantation drug, cyclosporine A (a natural, N-methylated cyclic peptide), which can be administered orally, Kessler reported that multiple N-methylation is a promising way to rationally improve key pharmacokinetic characteristics in peptides.

N-methyl scan of the cyclopeptidic somatostatin analog cyclo(-PFwKTF-), known as the Veber−Hirschmann peptide, improves not only oral bioavailability but also receptor selectivity.

Another interesting question is to what extent might the N methylation contribute to the bioavailability (the ADMET profile) in the amide of small molecules rather than peptides? For example, Tubulin-binding taxanes such as paclitaxel and docetaxel are important cancer chemotherapeutic agents. However, these drugs suffer from limitations such as poor aqueous solubility and oral bioavailability, emerging drug resistance, and the lack of blood-brain barrier permeability.

N-methyltaxol C (methylation of the C3′ amide of taxol C), a potential impurity in clinically used taxanes, showed improved bioavailability. This result demonstrates the utility of N-methylation to improve key pharmacokinetic characteristics in amides.

The making of hERG free molecules (The Role of Fluorine)

The unwanted hERG affinity could be removed by moderating 

1) basicity (control pka),

2) lipophilicity of the compound, and 

3) steric environment of the central nitrogen 

A paper in BMCL from Pfizer reported the pka, lipophilicity, independent optimization of hERG affinity for the CCR5 antagonist ‘Maraviroc’. The steric demand and the dipole generated by the difluoro moiety of 4 4’difluoro cyclohexyl group in maraviroc are clearly not tolerated within the hERG channel.

 

Overcoming hERG affinity in kinesin spindle protein inhibitor MK-0731 for the treatment of Taxane Refractory Cancer was achieved by making axial fluorine in the piperidine ring.

The rule of three and ADMET

Paul Gleeson from GSK has come up with a set of rules of thumb for the three crucial property of drug namely molecular weight, log P, and ionization state (which medicinal chemist comfortable and familiar with) that influence their ADMET behavior Such as Solubility, Permeability, Bioavailability, Volume of distribution, Plasma protein binding, CNS penetration, Brain tissue binding, P-gp efflux, hERG inhibition, and Cytochrome-P450. This study is vital for the pharmaceutical industry because up to 40 % of promising candidates fail in clinical trials due to unfavorable pharmacological properties in drug development. His study re-emphasizes the need to focus on a lower molecular weight and log P area of physicochemical property space to obtain improved ADMET parameters.