title: Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.
abstract: Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.
authors: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors: Paride
authors: P
authors: Liscio
authors: Andrea
authors: A
authors: Carotti
authors: Stefania
authors: S
authors: Asciutti
authors: Tobias
authors: T
authors: Karlberg
authors: Daniele
authors: D
authors: Bellocchi
authors: Laura
authors: L
authors: Llacuna
authors: Antonio
authors: A
authors: Macchiarulo
authors: Stuart A
authors: SA
authors: Aaronson
authors: Herwig
authors: H
authors: Schüler
authors: Roberto
authors: R
authors: Pellicciari
authors: Emidio
authors: E
authors: Camaioni
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D008156:Luciferases / Q000235:genetics; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000246:Adenosine Diphosphate Ribose; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D008156:Luciferases; D011724:Pyridazines; D011994:Recombinant Proteins; D038501:Tankyrases; D014230:Triazoles; C000588587:4-(2-(6-methyl-(1,2,4)triazolo(4,3-b)pyridazin-8-ylamino)ethyl)phenol; C418109:TNKS protein, human