Saturday, July 26, 2008

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 (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 (

Thursday, July 17, 2008

Fluorination reaction of aryl boranic acids

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.

Friday, July 11, 2008

The rule of three and ADMET

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.

Wednesday, July 2, 2008

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 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.