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

Llona-Minguez S, Ghassemian A, Baranczewski P, Desroses M, Koolmeister T, Artursson P, Scobie M, Helleday T

Med. Chem. Commun. 8 (7) 1553-1560 [2017-07-01; online 2017-07-04]

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. compound 29 MLM/HLM t1/2 = 113/105 min).

Drug Discovery and Development (DDD) [Collaborative]

PubMed 30108867

DOI 10.1039/c7md00230k

Crossref 10.1039/c7md00230k

pii: c7md00230k
pmc: PMC6072423