Design, Synthesis, CrystallographicStudies, and PreliminaryBiological Appraisal of New Substituted Triazolo[4,3-b]pyridazin-8-amine Derivatives as Tankyrase Inhibitors.

Searchingfor selective tankyrases (TNKSs) inhibitors, a new smallseries of 6,8-disubstituted triazolo[4,3-b]piridazineshas been synthesized and characterized biologically. Structure-basedoptimization of the starting hit compound NNL (3) promptedus to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), alow nanomolar selective TNKSs inhibitor working as NAD isostere asascertained by crystallographic analysis. Preliminary biological datacandidate this new class of derivatives as a powerful pharmacologicaltools in the unraveling of TNKS implications in physiopathologicalconditions. [ABSTRACT FROM AUTHOR]