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

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).

SUBMITTER: Llona-Minguez S

PROVIDER: S-EPMC6072423 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Llona-Minguez Sabin S Ghassemian Artin A Baranczewski Pawel P Desroses Matthieu M Koolmeister Tobias T Artursson Per P Scobie Martin M Helleday Thomas T

MedChemComm 20170704 7

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 t1/2 = 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. ...[more]

PMID: 30108867

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