Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.

Liscio P, Carotti A, Asciutti S, Karlberg T, Bellocchi D, Llacuna L, Macchiarulo A, Aaronson SA, Schüler H, Pellicciari R, Camaioni E

J. Med. Chem. 57 (6) 2807-2812 [2014-03-27; online 2014-02-18]

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.

Protein Science Facility (PSF)

QC bibliography QC xrefs

PubMed 24527792

DOI 10.1021/jm401356t

Crossref 10.1021/jm401356t

PDB 4M7B

mid NIHMS681657

pmc PMC4406096