Comparison of parent and metabolite in vitro cytochrome P450 Ki values for Pfizer clinical development candidates

Metabolite >4× More Potent than Parent (n = 0)Metabolite 1–4× More Potent than Parent (n = 4)Metabolite <1× Potent than Parent (n = 10)
PF-01 -(2×, O-desmethyl, P at 2D6 M at 1A2)PF-02 -(<1, N-desmethyl, 3A4)
PF-04 -(1×, N-desmethyl, 2B6)PF-03 -(<0.3, O-glucuronide, 2C9)
PF-04 -(1×, N-oxide, 2D6)PF-05 -(0.4, methyl catechol, 2D6)
PF-11 -(1×, N-desethyl, 2D6)PF-06 -(<0.3, N-desethyl, 3A4)
PF-07 -(<0.003, cleaved acid, 2D6)
PF-08 -(<0.01, cleaved acid (a), 3A4)
PF-08 -(<0.01, cleaved acid (b), 3A4)
PF-09 -(P and M inactive, alcohol)
PF-10 -(P and M inactive, N-desmethyl)
PF-12 -(0.2, hydroxy, 2C19)
  • P, parent; M, metabolite; (fold change potency, metabolite structure, cytochrome P450).