| Autor: |
Gustavo Saluste, Maria I Albarran, Rosa M Alvarez, Obdulia Rabal, Miguel Angel Ortega, Carmen Blanco, Guido Kurz, Antonio Salgado, Paolo Pevarello, James R Bischoff, Joaquin Pastor, Julen Oyarzabal |
| Jazyk: |
angličtina |
| Rok vydání: |
2012 |
| Předmět: |
|
| Zdroj: |
PLoS ONE, Vol 7, Iss 10, p e45964 (2012) |
| Druh dokumentu: |
article |
| ISSN: |
1932-6203 |
| DOI: |
10.1371/journal.pone.0045964 |
| Popis: |
A new chemical series, triazolo[4,5-b]pyridines, has been identified as an inhibitor of PIM-1 by a chemotype hopping strategy based on a chemically feasible fragment database. In this case, structure-based virtual screening and in silico chemogenomics provide added value to the previously reported strategy of prioritizing among proposed novel scaffolds. Pairwise comparison between compound 3, recently discontinued from Phase I clinical trials, and molecule 8, bearing the selected novel scaffold, shows that the primary activities are similar (IC(50) in the 20 to 150 nM range). At the same time, some ADME properties (for example, an increase of more than 45% in metabolic stability in human liver microsomes) and the off-target selectivity (for example, an increase of more than 2 log units in IC(50)vs. FLT3) are improved, and the intellectual property (IP) position is enhanced. The discovery of a reliable starting point that fulfills critical criteria for a plausible medicinal chemistry project is demonstrated in this prospective study. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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