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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

Liscio, Paride ; Carotti, Andrea ; Asciutti, Stefania ; Karlberg, Tobias LU ; Bellocchi, Daniele ; Llacuna, Laura ; Macchiarulo, Antonio ; Aaronson, Stuart A ; Schüler, Herwig LU orcid and Pellicciari, Roberto , et al. (2014) In Journal of Medicinal Chemistry 57(6). p.12-2807
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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publishing date
type
Contribution to journal
publication status
published
keywords
Adenosine Diphosphate Ribose/metabolism, Chromatography, High Pressure Liquid, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors/chemical synthesis, Humans, Indicators and Reagents, Luciferases/genetics, Mass Spectrometry, Models, Molecular, Molecular Conformation, Pyridazines/chemical synthesis, Recombinant Proteins/drug effects, Structure-Activity Relationship, Tankyrases/antagonists & inhibitors, Triazoles/chemical synthesis
in
Journal of Medicinal Chemistry
volume
57
issue
6
pages
6 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:84897418380
  • pmid:24527792
ISSN
1520-4804
DOI
10.1021/jm401356t
language
English
LU publication?
no
id
e19496e7-2ca5-4226-bbc6-803c7fc93977
date added to LUP
2024-11-21 17:55:30
date last changed
2025-07-05 12:26:59
@article{e19496e7-2ca5-4226-bbc6-803c7fc93977,
  abstract     = {{<p>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.</p>}},
  author       = {{Liscio, Paride and Carotti, Andrea and Asciutti, Stefania and Karlberg, Tobias and Bellocchi, Daniele and Llacuna, Laura and Macchiarulo, Antonio and Aaronson, Stuart A and Schüler, Herwig and Pellicciari, Roberto and Camaioni, Emidio}},
  issn         = {{1520-4804}},
  keywords     = {{Adenosine Diphosphate Ribose/metabolism; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors/chemical synthesis; Humans; Indicators and Reagents; Luciferases/genetics; Mass Spectrometry; Models, Molecular; Molecular Conformation; Pyridazines/chemical synthesis; Recombinant Proteins/drug effects; Structure-Activity Relationship; Tankyrases/antagonists & inhibitors; Triazoles/chemical synthesis}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{6}},
  pages        = {{12--2807}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-<i>b</i>]pyridazin-8-amine derivatives as tankyrase inhibitors}},
  url          = {{http://dx.doi.org/10.1021/jm401356t}},
  doi          = {{10.1021/jm401356t}},
  volume       = {{57}},
  year         = {{2014}},
}