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 (

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