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.