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.

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.