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 (http://dx.doi.org/10.1021/jm800386y).


1 comment:

boc Sciences said...

MK-0731 is a synthetic small molecule with potential antineoplastic activity. MK0731 selectively inhibits kinesin spindle protein (KSP), which may result in the inhibition of mitotic spindle assembly, induction of cell cycle arrest during the mitotic phase, and apoptosis in tumor cells that overexpress KSP. MK-0731