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American Chemical Society, Journal of Medicinal Chemistry, 19(56), p. 7651-7668, 2013

DOI: 10.1021/jm401067s

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Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-Chagas agents

Journal article published in 2013 by Jun Yong Choi, Claudia M. Calvet, Shamila S. Gunatilleke, Claudia Ruiz, Michael D. Cameron ORCID, James H. McKerrow, Larissa M. Podust, William R. Roush
This paper is available in a repository.
This paper is available in a repository.

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Abstract

A 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 of 0.65 µM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, that 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 (