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.