Structure-metabolism-relationships in the microsomal clearance of piperazin-1-ylpyridazines

Sabin Llona-Minguez; Artin Ghassemian; Pawel Baranczewski; Matthieu Desroses; Tobias Koolmeister; Per Artursson; Martin Scobie; Thomas Helleday

doi:10.1039/c7md00230k

Structure-metabolism-relationships in the microsomal clearance of piperazin-1-ylpyridazines

Medchemcomm. 2017 Jul 4;8(7):1553-1560. doi: 10.1039/c7md00230k. eCollection 2017 Jul 1.

Authors

Sabin Llona-Minguez¹, Artin Ghassemian¹, Pawel Baranczewski², Matthieu Desroses¹, Tobias Koolmeister¹, Per Artursson², Martin Scobie¹, Thomas Helleday¹

Affiliations

¹ Division of Translational Medicine and Chemical Biology , Science for Life Laboratory , Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden . Email: sabin.llona.minguez@scilifelab.se ; Email: thomas.helleday@scilifelab.se.
² Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP) , Science for Life Laboratory , Department of Pharmacy , Uppsala University , Uppsala , Sweden.

Abstract

In this study, we provide insight into the metabolic profile of a series of piperazin-1-ylpyridazines suffering from rapid in vitro intrinsic clearance in a metabolic stability assay using liver microsomes (e.g. compound 1 MLM/HLM t_1/2 = 2/3 min). Aided by empirical metabolite identification and computational predictive models, we designed the structural modifications required to improve in vitro intrinsic clearance by more than 50-fold (e.g. compound 29 MLM/HLM t_1/2 = 113/105 min).