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.

Fluorination of aryl boronic acids

Replacement of C-H bond with fluorine (C-F) has unique 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; also there may be functional groups that are not compatible with fluorination.

Recently, Ritter and co-workers reported a regioselective, functional group tolerant fluorination reaction of aryl boronic acids mediated by palladium complex. This process is ideally suited for introducing fluorine substituents at a late stage for aryl fluoride synthesis.

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.

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

Guest Post – Jagmohan Singh Saini

The whole drug discovery and development process is very time-consuming and expensive. It is now recognized that besides poor ADME (Absorption, distribution, metabolism, and excretion), cardiac toxicity is one of the killer factors for a molecule to be a drug. In recent years, several blockbuster drugs have been withdrawn from the market because of reports of sudden cardiac deaths. In all cases, long QT syndrome, characterized by the prolongation of the QT interval in ECG was responsible.

The prolonged duration of the cardiac action potential can be traced to one specific mechanism: blockage of Ikr current in the 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 a 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. 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

The ideal total synthesis of a natural product would proceed in one step and in 100% yield from commercially available starting material- this dream is increasingly driving natural product 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 and they made only the preferred mirror-image form, or enantiomer, of the molecule, instead of a racemic mixture containing equal amounts of both enantiomers. This methodology takes advantage of the intrinsic reactivity of the molecule's different functional groups.

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

Most biomolecules are "chiral", that is to say, they exist in two left and right-handed mirror-image forms. However, biology only uses one hand, i.e., it is "homochiral". Life on Earth is made of left-handed amino acids, almost exclusively. One of the greatest puzzles in biophysics is the question of why life on Earth is based on left-handed (L) amino acids? Moreover, the synthesis of single enantiomers (ee ~100%) is one of the most critical industry demands.

Recently Prof. Pedro Cintas described that fractional sublimation of chiral organic compounds improves ee substantially.

The reported results provide a beneficial protocol for the resolution of racemates. Additionally, it suggests that improvement of optical activity by such a 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 in the prebiotic world. Subsequent stochastic sorting of crystals of enantiopure compounds by natural agents might have generated highly enantiopure niches, which might be responsible for the prevalence of homochirality in nature.

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

The Histamine H4R receptor is the most recently identified G-protein coupled 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 mobilization and chemotaxis in mast cells.

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

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

Novel Reactions: Are anymore waiting to be Discovered?

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 contains only a minor improvement on a well-known reaction or a new application of an old technique.

Fluorine in Drug Discovery

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.

Replacement of hydrogen with Fluorine (F) in a pharmacologically active molecule can profoundly change the conformational preference due to its size difference and stereoelectronic effects.

1) F can enhance binding efficacy and selectivity in pharmaceuticals.

2) F substituents on ligands prefer to orient toward electropositive regions of receptor sites.

3) Distinct fluorofilic environment in proteins includes 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 is a promising strategy during the lead optimization stage of drug discovery. Fluorine substitution enhances physicochemical and adsorption, distribution, metabolism, and excretion properties and strengthens 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 repertoire for the specific introduction of Fluorine in an organic molecule.

The Negative Side of Boran

According to researchers Makoto Yamashita and his colleagues at the University of Tokyo, Japan, a molecule that hosts a negatively-charged boron atom could prove to be an exciting addition to the chemist's toolbox. Recently they have isolated the anion as its lithium salt.  

Lithium can partner with many boron's neighbors in the periodic table, such as nitrogen in lithium amide and carbon in methyllithium. However, 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.

This work opens the door to new pathways in boron chemistry that will substantially impact organic synthesis in general.

Ref: Makoto Yamashita and colleagues at the University of Tokyo, Japan. Science 2006, 314, 113.

Identification of novel therapeutic targets for HIV

Using a 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.