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      Design, Synthesis, Crystallographic Studies, and Preliminary Biological Appraisal of New Substituted Triazolo[4,3-b]pyridazin-8-amine Derivatives as Tankyrase Inhibitors

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          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.

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          Author and article information

          Journal
          Journal of Medicinal Chemistry
          J. Med. Chem.
          American Chemical Society (ACS)
          0022-2623
          1520-4804
          March 18 2014
          March 27 2014
          February 24 2014
          March 27 2014
          : 57
          : 6
          : 2807-2812
          Affiliations
          [1 ]Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy
          [2 ]TES Pharma, via P. Togliatti 22bis, 06073 Località Terrioli, Corciano, Italy
          [3 ]Mount Sinai School of Medicine, Dept. Oncological Sciences, 1425 Madison Avenue, New York, New York 10029 United States
          [4 ]Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden
          Article
          10.1021/jm401356t
          4406096
          24527792
          9ee4691e-c8d1-4aac-a991-9d8de0f661b1
          © 2014
          History

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