jm401067s_si_001.pdf (449.8 kB)
Rational Development of 4‑Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents
journal contribution
posted on 2016-02-18, 16:21 authored by Jun Yong Choi, Claudia
M. Calvet, Shamila
S. Gunatilleke, Claudia Ruiz, Michael
D. Cameron, James H. McKerrow, Larissa M. Podust, William R. RoushA new series of 4-aminopyridyl-based
lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51)
has been developed using structure-based drug design as well as structure–property
relationship (SPR) analyses. The screening hit starting point, LP10
(KD ≤ 42 nM; EC50 =
0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r,
and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts
(EC50 = 14–18 nM for 27i and 27r). Many of the optimized compounds have improved microsome
stability, and most are selective against human CYPs 1A2, 2D6, and
3A4 (<50% inhibition at 1 μM). A rationale for the improvement
in microsome stability and selectivity of inhibitors against human
metabolic CYP enzymes is presented. In addition, the binding mode
of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized
by X-ray structure analysis.