SYNTHESIZING IDEAS

Totally drug resistant TB

2012-01-22T18:40:00.000-08:00

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 wide spread 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 strain of existing Mtb which 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 the 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.

Nano reactions

2012-01-22T02:16:00.000-08:00

Recently, nanoporous materials have emerged as important and efficient heterogeneous catalysts for the organic transformations owing to their excellent textural characteristics including high surface area, large pore volume, and uniform pore size distribution, and its simplicity in workup and recyclability. The pore diameters are chosen to control the access of molecules to the catalytic reaction sites located inside the porous cavities. Only the molecules of certain sizes and chemical properties are selected and guided to the reaction centers where they are efficiently transformed to the desired products.

What's a PhD worth?

2012-01-20T05:28:00.000-08:00

Here's another article in the nature that makes some good points about the worth of PhD.

"The number of science doctorates earned each year grew by nearly 40% between 1998 and 2008, to some 34,000, in countries that are members of the Organisation for Economic Co-operation and Development (OECD). The growth shows no sign of slowing: most countries are building up their higher-education systems because they see educated workers as a key to economic growth. But in much of the world, science PhD graduates may never get a chance to take full advantage of their qualifications"

PhD program use to be for science-loving driven people and the world want more innovation from academic science to solve the problems.

Mycobacteria and the great wall

2012-01-10T02:52:00.000-08:00

Mycobcaterial cell wall is unique, thick waxy and hydrophobic in nature, which ensures its survival inside human macrophages by resisting oxidative damages.The waxy, highly impermeable nature of the wall provides the required defense mechanism against antibiotic agents, and the host organisms. A key component of the cell wall is mycolic acids. Mycolic acid accounts up to 60% of the dry weight of the organisms which means that most percentage of mycobacteria is a cell wall. Thorough understanding of the influence of polarity on the drug penetration in to highly impermeable mycobacterial cell wall will guide us to improve permeability.

The permeation ability of a lipophilic molecule is inversely related to the fluidity of the cell wall, which decreases as the length of fatty acids in the mycolic acids layer increases. The permeability barrier presented by this cell envelope is also thought to be a reason why many common antibiotics are ineffective against mycobacteria. Lipophilic drugs, such as fluoroquinolones or rifamycins, pass more easily through the lipid-rich cell wall and thus are more active.

It is clear that, depending on the library screens towards compounds with a particular physicochemical parameter could actually be detrimental and decrease the diversity of finding new anti-TB drugs.

Enoyl reductase: One target, Two major Global Threats

2011-04-19T09:19:00.000-07:00

Tuberculosis and Malaria are two major global threats both account 5 million deaths annually (mostly in poor 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 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 responsible 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 enzyme, has been repeatedly validated as an effective antimicrobial target (eg INH, diazoborines , triclosan , and thiolactomycin)

Triclosan, the ENR inhibitor showed very good activity against both organisms. Targeting ENR with new class of compounds may yield new Drug for the use against these devastating pathogens

The Future of Drug Discovery

2011-03-28T18:50:00.000-07:00

The new technologies promise to fill drug development pipeline with small molecule candidates is unfulfilled, so pharmaceutical industry is currently undergoing rapid changes, they are moving aggressively into large molecule 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 future. One of the major Challenges for medicinal chemist is small molecule inhibitors of protein-protein interactions.

Toxicophores Simplified

2011-03-06T01:40:00.000-08:00

Bottom of the pyramid

2010-07-22T06:08:00.000-07:00

Indian patients no longer have to wait for the drug to become generic. Recently BMS and Astra Zeneca launched their new oral pill Saxagliptin (DDP 4 inhibitors ) to treat type 2 diabetes in India, less than one year after its US approval. India is the first Asian country where the drug is available at affordable price which is 1/5 of its US cost

Pharma Companies are now realizing that there is tremendous opportunity in emerging markets, not only because they entail low operating costs but also because of the fast growing middle class population, they are emerging as a huge market for global products. As the economy grows life style associated diseases grow along with it, Therefore companies try to launch drugs for these life style related diseases such as diabetes. Forecasts suggest 50% of business will be in those markets by 2020. Acquisition of Daichi to Ranbaxy and Abbot by Piramals make it clear that big pharma companies want to make a strong market presence in India.

“Rather than trying to find a use for approved medicines that were developed for a non-Asian phenotype, the move is to discover and develop medicines specifically to treat Asian diseases,” explains Paul Bolno, VP of Oncology R&D, Business Development at GSK. Here is a Nature article

But it will take a long time for the local doctors here in Inida to stop giving the pills without any label and any expiry dates on it. (pic; which I was given by a local hospital for a mild fever, you have to remember the tablets by its color)

PhD fellowships

2010-07-21T05:21:00.000-07:00

Faculty of Pharmaceutical Sciences, University of Copenhagen is announce that eight PhD fellowships will be available from 1 October 2010.You can read more about here

Kinase Inhibitors: beyond Oncology

2010-04-27T01:14:00.000-07:00

We just 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 the result of tissue distribution of kinase inhibitors. Imatinib has been highly successful in the treatment of both chronic myelogenous leukaemia , gastrointestinal stromal tumours and other cancers,but associated with severe, cardio toxicity. 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 be effective at inhibiting number of inflammatory pathways.

Almost all the p38MAPK inhibitors having hepatotoxicity issue, SCIO 469 and Arry 797 initially developed for RA but went in to clinic for post operative dental pain , here the potential toxicity problems won’t show up because the drugs is used only for a very short time, Are BMS-582949 and VX 702 still in development? Hundreds of millions have been spent by different companies 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 the Phase III

Naked Discovery

2010-04-16T05:17:00.000-07:00

Unlike the highest secrecy in closed door traditional drug discovery by pool of rigid mindset scientists,
the Open Source Drug Discovery (OSSD) Program aims to address the issue by attempting to capture the youngest and brightest minds around the globe to be a part of developing drugs to treat drug resistant TB, 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 in the development of 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 comprehensive mapping of the Mtb genome 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

2010-03-25T02:07:00.000-07:00

Drug discovery is a lengthy, high risk and costly endeavor; many strategies exist to accelerate the development process to provide the highest quality of the candidate. The diminished interest in Natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry, but these new technologies promise to fill 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 (valeriana officinalis) 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 which is a major constituent of common valerian is a potent modulator of GABA-A receptors. Inorder to develop a broader understanding of structural requirements for GABA-A modulatory activity of valerenic acid Kopp s et al (chem med chem) synthesized several analogues, 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 is 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

Big is good?

2010-03-03T20:13:00.000-08:00

The movement of big pharma into biologics understandably has a direct effect on pharmaceutical landscape. Companies shows a diminishing portfolio revenue from small molecules drugs, primarily because of patent expiration on blockbuster drugs (small molecules) and also due to 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 include 19 new molecular entities (NMEs) and six novel biologics. In 2008 FDA approved 21 NMEs and 3 novel biologics. A substantial improvement in biologics approvels in 2009. (fig.1, Nature medicine,139,16,2010) and it is expected to take over from small molecule field in the coming years( fig 2, Nature reviews/drug discovery ), But 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 need if they plan on carriers in this area.

Kill the Bugs, Selectively

2009-11-12T01:43:00.000-08:00

“Today, we have tuberculosis drugs you have to take for 9 months, why can’t we find one that work in three days”
- Bill Gates.

Tuberculosis (TB) is a chronic contagious disease caused by Mycobacterium tuberculosis (M.tb), is one of the leading caused 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 life time. 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 are spreading throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts in the development of 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 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 a brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy.This findings may lead to drugs that destroy TB in dormant stage of lifecycle.

Poor Pigs

2009-09-05T02:39:00.000-07:00

A new strain of swine flu influenza a H1N1 virus is spreading around the globe. The WHO declared 2009 swine flu pandemic - First Phase 6 Influenza pendemic Since 1968.

(_)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used in the treatment of both type A and type B human influenza,Currently the most effective drug for the treatment of Influenza. But the unmet supply of this drug demand 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. It is known that several labs have already reported new methods in making Tamiflu without shikimic acid. But it is very difficult to evaluate academic syntheses from the standpoint of potential as a manufacturing process because they have not been developed for the large-scale operation. Considering the amount of Tamiflu required worldwide, there is an urgent demand to improve the production process.

Here is the retro synthetic analyse for the short cut synthesis of Tamiflu.
This syntheis intiated by oxa-Michael addition of alcohol to acrolin, which was reported by Zhang et al,

Going Right-handed

2009-07-18T02:52:00.000-07:00

Why we are made of only right-handed sugars? That’s long been one of the biggest puzzles in understanding how life began, and this origin of homochirality in sugars and amino acids have been intrigued researchers for decades. So for, convincing theory and experiment on the origin of homochirality are still lacking.

Armando Co´rdova and coworkers at Stockholm University, Sweden.
used amino acid as catalyst for the formation of hexoses sugars with >99 ee.
Hexose’s have been suggested as building blocks of ancient RNA. It may be an example of the theoretical basis for the evolution of homochirality of sugars(right handed configuration) in the prebiotic world.

Andrew Pohorille and Chenyu Wei at NASA Ames Research Center
found that (JACS,2009) ribose permeates membranes an order of magnitude faster than its diastereomers. On this basis it was hypothesized that differences in membrane permeability to aldopentoses provide a basis for preferential delivery of ribose to primitive cells for subsequent selective incorporation into nucleotides and their polymers.

D ribose (right handed sugar) polynucleotide tend to form right handed helices, What is the neutral macroscopic cause that gave rise to preference of both right handed helical nucleic acids and proteins on earth?

Y J He et al suggested that a net natural chiral right-handed helical force field, produced by the Earth’s orbital chirality (EOC) could affect the stability of molecule helical enantiomers and make the right-handed helical enantiomers more stable than their left- handed enantiomers. So, terrestrial living systems must select both right-handed nucleic acids based on D-sugars and right-handed proteins based on L-amino acids.

This homochirality can be observed on the macroscopic scale, for example, in the helical chirality of snail shells (preferred right-handed) and the helical winding of some kind of plants.

May be full understanding of life and its evolution will never be possible.
But this will not certainly stop scientist to seek the secret of the origin of life.
Whitesides recently expressed the current state of understanding of origin of life in frank words

Most chemists believe, as do I, that life emerged spontaneously from mixtures of molecules in the prebiotic Earth.How? I have no idea. Perhaps it was by the spontaneous emergence of “simple” autocatalytic cycles and then by their combination. On the basis of all the chemistry that I know, it seems to me astonishingly improbable

GABA receptors as RA and Pain Targets? The Missing Link

2009-06-29T01:44:00.000-07:00

Kelley et al proposed a hypothesis for an inefficient GABA signalling system that resulted in unchecked pro-inflammatory cytokine production via the p38 MAP kinase pathway. p38 is a kinase target that regulates the production of inflammatory cytokines TNF, IL-1, IL-6 and PGE2.
TNF, IL-1 and IL-6 are well-validated cytokines for controlling inflammation in rheumatoid arthritis (RA). PGE2 is the important mediator for inflammatory pain. But most of the p38 projects failed to deliver drugs due to CNS toxicity, Is this CNS side effects linked to GABA?

The research team led by Ulrich Zeilhofer used genetically altered mice in experiments to target the GABA receptors that control spinal pain relay, they showed that the non-sedative benzodiazepine ligand L- 838417 (a GABA receptor ligand) is highly effective against inflammatory and neuoapathic pain.

Clomethiazole edisilate is a drug that act on GABA receptor, which inhibits the p38 MAPK too. The small molecule doesn’t have the structural features of the other p38 inhibitors have, seems to provide the support for this hypothesis. The task is to find which subtype of GABA responsible for the chronic pain.

However no direct link has been reported between GABA and p38 MAPK.
The role of GABA in the development of RA and pain will encourage the further integration of Immunology in to clinical neuroscience. These finding may provide a rational basis for the development of subtype selective GABAergic drugs for the treatment of RA and chronic pain.

Drug Optimization (Lead Optimization?)

2009-05-13T06:11:00.000-07:00

Pharmaceutical Companies are trying to fill their drug portfolio by optimizing the marketed drugs. Most of the recently launched drugs that are structurally similar to already known drugs, with only minor differences.The most common drug optimization methods are:

1. Reactive metabolites

A good example of this is venlafaxine (Effexor) and desvenlafaxine ( Pristiq). Desvenlafaxine is the metabolite of venlafaxine. The difference is that desvenlafaxine having O-H instead of O-Me.

2. Switching a Hydrogen atom with heavier isotopes

Pharma companies hopes that the deuterated drug survives longer in the body and fewer side effects, because the Deuterium can make stronger chemical bond than Hydrogen.

3. Racemic switching

Racemic switching is the redevelopment in a single enantiomer from a drug that was fist approved as a racimate, a better example is the Nexium. It is a predecessor Prilosec, a mixture of both S and R isomers. When Prilosec’s patent expired in 2001, the drug maker was ready with Nexium, which contains only the S-isomer.

The proliferation of "me-too" drugs leads to beneficial cost reductions.
But in the end, the real question is about pharmaceutical innovation. While “me too” fill the development pipeline; the creativity is fading away in the Art of Drug Discovery.

Rule of attraction

2009-04-08T07:10:00.000-07:00

The role of fluorine in Ligand – Protein interaction has been well studied, but much less known about the non-bonding interaction of chlorine and bromine with protein.
A new paper (Angew. Chem. Int. Ed 2009, 48, 2911) from Matter demonstrates the non-covalent interaction between the chlorine or bromine and the aromatic ring in protein.

This Cl/Br…pi interaction might be general use in structure based design towards interaction for aromatic amino acids. It is clear that systematic halogen scan (F, Cl and Br) in the lead structure will be a useful strategy for the lead optimization, not only block the metabolic labile position but also to strengthen protein-ligand binding interaction.

Fluorine in Drug Development

2009-04-02T23:13:00.000-07:00

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 which allows three- dimentional quantitative determination of the distribution of radioactive whin the human body.The relatively long half life, high % of β emmision and relatively low positron energy maks 18 F makes it is most favourabe for the Positron emission tomography (PET) Studies.
F MR allows detection of the presence of the target, in vivo, includeing assessment of the presence of targets, as well as quantification of their spatial and temporal distribution.

(fig. 2)

F MR - Fluorine Magnetic Resonance.
PET- Positron emission tomography.

Lead Finding

Once the target is chosen and identified, 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 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 in to molecules are centred 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.
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 reache its targets is important in drugs 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 a prefect because plasma levels of compound often do not reflect concentrations in specific tissue, because of the presence of physicochemical barriers such as between blood and brain.
Proton Emission tomography provide the 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’

2009-03-20T04:21:00.000-07:00

Recently Aronov from Vertex pharmaceuticals proposed (JMC, 2008, 51,1214) a general ‘rule of thumb’ termed the 2-0 rule of kinase likeness to discriminating kinase compound from general compound .

For kinase activity the molecule should have

1) One or more hetero aromatic nitrogen’s,
2) One or more hetero aromatic NH group,
3) It contain one or more aniline,
4) And it contain one or more nitriles.

78 % of the kinase compound pass the 2-0 rule.

Are Protein Kinase Drug Targets ?

2009-03-13T22:45:00.000-07:00

20 –25% of druggable genome consists of kinase and this target account 20-30% of the drug discovery program of many companies.

Chem Med Chem 2007, 2,1116

Kinase inhibitors in the market include Tykerb® , Sprycel®, Sutent®,Nexavar®, Tarceva®, Iressa®, and of course Gleevec®.
D&MD Report 2005 shows that, Kinase targeted therapies 12.7bn 2005 to 58.6bn 2010, The key word search for kinase inhibitors 1281 patent filed in 2007 alone.

So what is the problem with kinase? Staurosporine that hits almost every kinase out there is going to be undoubtedly gratuitously toxic, Is "lake of selectivity" is the problem?
The real problem with kinase inhibitors is that toxic outcome may be the result of tissue distribution of orally administered kinase inhibitors.

The Answer is Yes! but,difficult one..

Phosphonium Coupling

2009-01-29T03:27:00.000-08:00

A recent review article,Eur. J. Org. Chem. 2009, 461-479 by Kang F. et al., describes a new, efficient, chemoselective and versatile phosphonium mediated tautomerization-activation methodology for tautomerizable heterocycles.

Phosphonium Coupling affords the direct C-N, C-S, C-O and C-C bond formation of electron deficient heterocycles with various nucleophiles (with boronic acid for C-C) via C-OH bond activation using phosphonium salts.
The author believes that the reactivity of the C-OP+ is similar to that of C-Br, so that direct bond formation can be achieved via either SNAr displacement or transition metal catalyzed cross coupling under mild condition.

This Phosphonium Coupling leads to the most efficient synthesis of biologically important nucleosides from unactivated, unprotected, commercially available starting materials.

N-Methylation and Oral Bioavailability.

2008-09-20T01:11:00.000-07:00

Inspired by the excellent pharmacokinetic profile of transplantation drug, cyclosporine A (a natural, N-methylated cyclic peptide) which can be administered orally, Kessler( Angew. Chem. Int. Ed 2008, 47, 2595.) 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, not only improve oral bio availability but also the receptor selectivity.

Another interesting question is to what extent might the N methylation contribute to the bioavilability (the ADMET profile) in 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)

2008-07-26T00:16:00.000-07:00

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 (16, 4633) 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 clearely not tolerated with in the hERG channel.

Overcominig hERG affinity in kinesin spindle protein inhibitor MK-0731 for the treatment of Taxane Refractory Cancer was achived by making axial fluorine in the piperidine ring (http://dx.doi.org/10.1021/jm800386y).

This is not Suzuki...

2008-07-17T01:35:00.000-07:00

Replacement of C-H bond with Fluorine has special advantages in drug development
and tracers for Positron Emission Tomography (PET), a powerful technology for noninvasive molecular imaging.

Introducing Fluorine group directly onto a saturated ring system is very difficult and there also may be functional groups that are not compatible with fluorination.

Recently Tobias Ritter reported (DOI: 10.1002/anie.200802164) a regioselective, functional group tolerant Fluorination reaction of aryl boranic acids mediated by palladium complex.

The rule of three and ADMET

2008-07-10T22:07:00.000-07:00

Paul Gleeson from GSK has come up with a set of rules of thumb (DOI: 10.1021/jm701122q) for the three important 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 important for pharmaceutical industry because in drug development up to 40 % of promising candidate failing in clinical trails due to unfavorable pharmacological properties.
His study re-emphasizes the need to focus on a lower molecular weight and log P area of physiochemical property space to obtain improved ADMET parameters.

Killer factor for a molecule to be a drug - hERG Channel Inhibition

2008-07-02T01:07:00.000-07:00

The whole Drug Discovery and development process is very time consuming and expensive. It is now recognized that beside poor ADME (Absorption, distribution, metabolism and excretion) cardiac toxicity is one of the killer factor for a molecule to be a drug. In recent years, numbers of blockbuster drugs have been withdrawn from market because of report of sudden cardiac deaths. In all cases, long QT syndrome, characterized by the prolongation of the QT interval in ECG was responsible.
Prolonged duration of cardiac action potential can be traced to one specific mechanism: blockage of Ikr current in heart. This current is conducted by tetrameric pores with the individual subunit encoded by human ether-à-go-go related gene (hERG). Blockage of hERG K+ channel is widely regarded as prominent cause of drug induced QT prolongation making early detection of compounds with this undesirable side effect an important objective in the pharmaceutical Industry.

Perhaps owing to the unique shape of the ligand-binding site and its hydrophobic character, the hERG channel has been shown to interact with pharmaceuticals of widely varying structure, often at concentrations similar to the levels of on-target activity of the respective compounds.
The homology model of hERG Channel clearly shows that and Phe656 and Tyr652 appeared to be the primary interaction points.The current consensus implicates Phe656 in π-stacking interactions with the ligands, whereas Tyr652 is thought to participate in a cation–π interaction with the protonated basic nitrogen present in most of the reported hERG blockers.

Structural model of hERG channels. (a) Key elements of hERG channel topology illustrated using the X-ray structure of KvAP. Two of the four subunits comprising the tetrameric channel are shown. (b) Model of the pore portion of hERG channel. The P-S6 fragment is shown for a dimer. Aromatic residues Phe656 and Tyr652 are critical for hERG block by most known small molecule ligands. Polar residues Thr623 and Ser624 modulate the binding potency for a number of reported hERG blockers.
A hERG blocker is represented schematically based on published evidence.
One or two hydrophobes interact with Phe656, a positive charge is stabilized by cation–π interaction with Tyr652, and the generally hydrophobic tail contains an acceptor able to interact with the polar residues on the loop that connects the pore helix to the selectivity filter.

Chemistry Unprotected

2008-06-14T00:08:00.000-07:00

The ideal total synthesis of a natural product would proced in one step and in 100% yield from commercially available starting material- this dream is increasingly driving natural products synthesis as a science.
Dr Phil Baran and colleagues at Scripps Institute, La Jolla, California, promises to generate natural products in much larger amounts than conventional methods, making biological testing much easier for drug discovery scientists, Most total syntheses, make liberal use of protecting groups. Adding and removing protecting groups can add many steps to a synthesis, cutting overall yields drastically.
Baran's team have now made a collection of marine natural products without using a single protecting group. Instead, they take advantage of the intrinsic reactivity of the molecule's different functional groups.
Fig(-)-fisherindole to (+)- welwitindolinone The reactions were enatioselective - they made only the preferred mirror-image form, or enantiomer, of the molecule, instead of a racemic mixture containing equal amounts of both enantiomers. They take advantage of the intrinsic reactivity of the molecule's different functional groups.
DOI: 10.1002/anie.200702455

Why we are made of only left-handed amino acids? A molecular concept of Life.

2008-03-15T02:18:00.000-07:00

kshetra-kshetrajnayor jnanam -Bhagavad Gita (13.3).
Most biomolecules are "chiral", that is to say they exist in two left and right -handed mirror image forms. But biology only uses one hand, i.e. it is "homochiral". Life on Earth is made of left handed amino acids, almost exlusively. One of the greatest puzzles in biophysics is the question of why life on Earth is based on left-handed (L) amino acids?
Recently Prof. Pedro Chintas (Angew. Chem. Int. Ed. 2008. 47. 2-5.) described that fractional sublimation of enantiomeric excess(ee) compounds may improve substantially a small ee. (This results a useful protocol for resolving racemate, and suggest that the improvement of optical activity attained by such thermal process could be more efficient than or at least an alternative to, spontaneous crystallization of suitable compounds)

He conclude that sublimation should be regarded as a reasonable mechanism for the formation of optically active crystals. These optically enriched crystals of enantiopure compounds easily conducted by natural agents might have generated highly enantiopure niches in the prebiotic world.

Molecular evolution might lead to life but it is not scientifically valid because life is a non- physical, non-chemical entity.

The Histamine H4 Receptor : Drug Discovery in the Post-genomic Era.

2008-03-08T00:53:00.000-08:00

The Histamine H4R receptor is the most recently identified G-protein couple receptor, with little homology to the classical pro inflammatory histamine H1 or the histamine H2 receptor, and some 35% homology with H3 receptor.

The high expression of the histamine H4 receptor in cells of hemopoietic lineage and immune cells suggests that this new histamine receptor plays a role in inflammatory and immune responses. Activation of the Histamine receptor can mediate calcium mobilisation and chemotaxis in mast cells.

Preliminary studies on the H4R and specific antagonist (JNJ 7777120 - Johnson & Johnson, VUF6002-Janssen Pharma.) suggests that another rich vein of histamine receptor therapeutics, likely to generate more blockbusters and medical break throughs, could be on the horizon.

Nature Reviews Drug Discover,7, 41-53, 2008, Trends Pharmacol. Sci. 26, 462-469, 2005

Novel Reactions: Are anymore waiting to be Discovered?

2008-02-15T23:35:00.000-08:00

Inspired by Barton's landmark total synthesis of Usnic acid, a method was devised by Baran for the direct oxidative coupling of indoles and pyrroles to a range of carbonyl compounds. ( Baran et al, J. Am. Chem. Soc. 2007, 129, 12857-69 )

when one examines the piece of work to which such a description has been applied it often turns out to contains only a minor improvement on a well known reaction or a new application of old technique.

F in Drug Discovery

2008-02-01T23:00:00.000-08:00

The importance of Fluorine in medicinal chemistry is well recognized. Indeed, an increasing number of drugs on the market contain Fluorine, the presence which often is of major importance to activity. A recent review article (Chem. Soc. Rev., 2008, 37, 320) by Sophie Purser describes the role of Fluorine in medicinal chemistry.

Substitution of H by F can profoundly change the conformational preferences of small molecules because of small size and streoelectronic effects.
F can enhance binding efficasy and selectivity in pharmaceuticals.
F substituents on ligands prefer to orient toward electropositive regions of receptor sites.
Distinct fluorofilic environment in proteins include the ubiquitous peptide bonds, which undergo multipolar C-F…H-N, C-F..C=O and C-F..H-C interaction.

Systematic fluorine scans of ligands as a promising strategy in lead optimization, not only to enhance physicochemical and adsorption, distribution, metabolism, and excretion properties, but also to strengthen protein-ligand binding interaction.

The effects of Fluorine substitution expands, further applications in drug discovery will emerge.Modern Fluorine Organic chemistry has dramatically widened the synthetic repetoire for the specific introduction of F in the organic molecule.

The Negative Side of Boran

2008-01-26T23:30:00.000-08:00

A molecule that hosts a negatively-charged boron atom could prove to be an exciting addition to the chemist's toolbox, according to researchers (Makoto Yamashita and colleagues at the University of Tokyo, Japan. Science 2006, 314, 113.) who have isolated the anion as its lithium salt.
Lithium can partner many of boron's neighbours in the periodic table, such as nitrogen in lithium amide, and carbon in methyllithium. But there have been no direct observations of the equivalent boryllithium compounds containing a negative boron atom. This type of boron anion shares the same number of valence electrons as its popular carbon cousin, the N-heterocyclic carbene. The Tokyo team demonstrated boryllithium's nucleophilic prowess in reactions with n-butyl chloride and benzaldehyde.

The work opens the door to new pathways in boron chemistry that will have a substantial impact on organic synthesis.

Identification of novel therapeutic targets for HIV

2008-01-19T20:39:00.000-08:00

Using functional genomic screen, researchers at Harvard Medical School have identified 273 proteins that the AIDS virus needs to survive in human cells, opening up new potential targets for drugs. Their work, published online on 10th Jan. by Science, used RNA interference to screen thousands of protein-making genes; previously, scientists had identified only 36 human proteins that the virus uses to break into cells, hijack their machinery and start reproducing.

The virus, which is itself only a short string of genetic material inside a protective capsule, can make only 15 proteins, so it has to adopt human proteins to its own use. Many of the proteins identified by the screen are already known to be important to cells in the immune system, which is the port of entry for H.I.V.

xDNA: A New Genetic System?

2007-11-16T03:32:00.000-08:00

Professor Eric Kool and his co-workers have developed " eXpanded DNA " dubbed "xDNA". The synthetic xDNA is expanding by adding benzene molecule to the base on the nucleotides and is a bit longer than regular 'B' form.

Unlike natural DNA, the expanded DNA is fluoresent and is considerably more stable when subjected to higher temperatures. Its unusual fluorescent properties could make it useful as a probe or diagnostic marker.

Is xDNA also capable of replicating? That's something Kool hopes to find out. Experiments with xDNA are expected to provide new insight into the behavior of natural DNA.

E. Kool, et al. Angew. Chem Int. Ed., 44, 3118-3122 (2005), JACS , 128, 9219-9230 (2006).

The solvent makes the difference

2007-11-09T23:55:00.001-08:00

The solvent surrounding the chiral molecule create a chiral shell (Chiral Imprint). The chirooptical properties can orginate mainly from the chiral solvent shell rather than from the chiral solute. For example, (S)-methyloxirane has a positive optical rotation in water, but has a relatively strong negative value in benzene (P. Mukhopadhyay et al Angew Chem Int Ed 2007, 46, 6450-6452). Computational experiments by J Neugebauer Angew Chem Int Ed 2007, 46, 7738-7740 shows the presence of the solute imprints a chiral structure on the inner solvation shell.

Cyanation of aryl halides

2007-09-26T03:33:00.000-07:00

There are several methods available for the cyanation of aryl halides. However a common problem with many of the more traditional methods is that they are very toxic# One method to full fill these criteria has been around for a while (Weissman S A et al, J. Org. Chem.2005, 70, 1508-1510.) Ligand- free, Palladium- catalyzed cyanation of aryl halides.Potassium hexacyanoferrate(II) has used as cyanide source. This result increase the list of metal catalyzed reactions that can be performed without ligand.

The advantage of this method is obvious, in contrast to other cyanating agents potassium hexacyanoferrate(II) is less poisonous# and can be handle without special precaution, due to the slow release of cyanide ions a significantly improved the catalytic productivity compared to previously know procedures in achieved.

#( KCN is extremely toxic (LDL0(oral, human) =2.86mg Kg-1 and develop HCN on contract with acidic water. K4[Fe(CN)6] is non toxic and used in food industry for metal precipitation in wine. Also it has been used as anti agglutinating auxiliary for NaCl (table salt). It is soluble in water without decomposition. Schareina T et al, Chem Commun., 2004, 1388-1389.)

Myers Asymmetric Alkylation

2007-09-08T00:30:00.000-07:00

Psuedoephedrine is a chiral auxiliary used for the synthesis of enantiomerically enriched carboxylic acid, aldehyde, alcohol and ketones.
Both enantiomers of pseudoephedrine are inexpensive and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective alkylations with a wide range of alkyl halides.

Advantages of using psuedoephedrine as chiral auxiliary,

• Enolate of pseudoephedrine amide undergo efficient and high diastreoselective alkylation with wide variety of alkyl halides.
• High enantiometrically enriched carboxylic acids, alcohols, aldehydes and ketones
• Large scale/ Preocess application ( low cost of auxiliary, crystallinity of starting materials and products, no carcinogenic solvents.)

Ref.: Myers, A.G. et al., J. Am. Chem. Soc., 1997, 119 , 6496

"Racemic Switch"

2007-09-07T07:27:00.000-07:00

A "racemic switch" is the redevelopment in single-enantiomer form of a drug that was first approved as a racemate. Sometimes, the pharmaceutical activity is in only one enantiomer and the other is inactive, or the "other" enantiomer has a different kind of activity from the first.
Omeprazole

Omeprazole is a Antiulcer drug (AstraZeneca) .It was marketed in U.S. as a racemic drug in 1995. The patent ran out in 2002. Since pharmacological property lies in (S)-enantiomer, the company has patented now (S)-enantiomer.

Reduction of amino acids

2007-05-21T00:38:00.000-07:00

There are many ways to reduce amino acids to amino alcohols, using sodium boro hydride and Iodine in THF is an excellent process.
which is not only non expensive and safety perspective but the work up is much easier (compared to LiAlH4) Iodine oxidizes the hydride giving a mole of H2 and generating BH3 in situ.
All that borane actually the stuff that reduce the acid to alcohol

Organic Synthesis: Problems

2007-01-16T04:52:00.000-08:00

Here are some links to the best organic synthesis problems on the web
(some even supply answers)

Tohru Fukuyama's Group:
http://www.f.u-tokyo.ac.jp/~fukuyama/index-e.htm

Steven Ley's Group:
http://leygroup.ch.cam.ac.uk/Education/education.htm

David Evans' Group:
http://daecr1.chem.harvard.edu/problems/