Pyrazolo[3,4-c]pyridazines as Novel and Selective Inhibitors of Cyclin-Dependent Kinases
- 8 October 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (22), 6843-6854
- https://doi.org/10.1021/jm058013g
Abstract
Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.Keywords
This publication has 22 references indexed in Scilit:
- Pharmacological inhibitors of glycogen synthase kinase 3Trends in Pharmacological Sciences, 2004
- The Protein Data BankNucleic Acids Research, 2000
- A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic MoleculesJournal of the American Chemical Society, 1995
- A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP modelThe Journal of Physical Chemistry, 1993
- An unbounded systematic search of conformational spaceJournal of Computational Chemistry, 1991
- Semianalytical treatment of solvation for molecular mechanics and dynamicsJournal of the American Chemical Society, 1990
- Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanicsJournal of Computational Chemistry, 1990
- Synthesis and Reactions of Some Pyridazine Derivatives Synthese und Reaktionen einiger Pyridazin-DerivateArchiv der Pharmazie, 1990
- Fluoronaphthyridines and quinolones as antibacterial agents. 1. Synthesis and structure-activity relationship of new 1-substituted derivativesJournal of Medicinal Chemistry, 1989
- Extensions of the hydrazone and Beckmann rearrangementsThe Journal of Organic Chemistry, 1982