VX-984 is a novel, small molecule inhibitor of DNA-dependent protein kinase (DNA-PK). Late stage analogues prepared during the discovery of VX-984 were predominantly metabolized <i>in vitro</i> by aldehyde oxidase (AO). Several approaches were attempted to mitigate this metabolism, including direct blocking of the metabolic site, steric shielding of the metabolic site, electronic modulation, and ring modification. The use of deuterium to exploit the kinetic isotope effect ultimately led to VX-984, a compound that shows significantly less metabolism by aldehyde oxidase<i> in vitro</i> than its proteo analogue. The various strategies to mitigate metabolism by AO will be discussed and compared.

Discovery of VX-984: Mitigation of aldehyde oxidase metabolism through the use of targeted deuteration

251st National Meeting (2016)

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