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,

Going Right-handed

Why are we made of only right-handed sugars? That has long been one of the biggest puzzles in understanding how life began, and this origin of homochirality in sugars and amino acids has 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 a 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 sugars' homochirality (right-handed configuration) in the prebiotic world.

Andrew Pohorille and Chenyu Wei at NASA Ames Research Center found that 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 tends to form right-handed helices; what is the neutral macroscopic cause that gave rise to the 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 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, the helical chirality of snail shells (preferred right-handed) and the helical winding of some kind of plants. 

Maybe a complete understanding of life and its evolution will never be possible. However, this will not certainly stop scientists from seeking the secret of the origin of life. Whitesides recently expressed the current state of understanding of the 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." 

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GABA receptors as RA and Pain Targets? The Missing Link

Kelley et al. proposed a hypothesis for an inefficient GABA signaling 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), and PGE2 is an essential mediator for inflammatory pain. However, most of the p38 projects failed to deliver drugs due to CNS toxicity. Are these 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 neuropathic pain. Clomethiazole edisilate is a drug that acts on GABA receptor, which inhibits the p38 MAPK too. This small molecule does not have other p38 inhibitors' structural features, which seems to support 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 RA and pain development will encourage further integration of Immunology in clinical neuroscience. These findings may provide a rational basis for developing subtype-selective GABAergic drugs to treat RA and chronic pain.

Drug Optimization

 

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

1. Reactive metabolites: 

An excellent 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. Deuterated Drugs: 

Switching a hydrogen atom with a heavier isotope such as deuterium, pharma companies hope that the deuterated drug survives longer in the body and fewer side effects because it can make a stronger chemical bond than hydrogen. 

3. Racemic switching: 

Racemic switching is the redevelopment in a single enantiomer from a first approved drug as a racemate; 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 drugmaker was ready with Nexium, which contains only the S-isomer. 

The proliferation of "me-too" drugs leads to beneficial cost reductions. However, in the end, the real question is about pharmaceutical innovation. While “me too” fills the development pipeline, the creativity is fading away in the art of drug discovery?

Rule of attraction

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.