95211-68-0Relevant academic research and scientific papers
Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode
Kranz, Michael,Wall, Michael,Evans, Brian,Miah, Afjal,Ballantine, Stuart,Delves, Chris,Dombroski, Brian,Gross, Jeffrey,Schneck, Jessica,Villa, James P.,Neu, Margarete,Somers, Don O.
experimental part, p. 5336 - 5341 (2009/10/23)
A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1-2 A. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design.
Parallel synthesis and biological evaluation of 5,6,7,8- tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one cytotoxic agents selective for p21-deficient cells
Jennings, Lee D.,Kincaid, Scott L.,Wang, Yanong D.,Krishnamurthy, Girija,Beyer, Carl F.,McGinnis, John P.,Miranda, Miriam,Discafani, Carolyn M.,Rabindran, Sridhar K.
, p. 4731 - 4735 (2007/10/03)
A novel series of inhibitors of cancer cell proliferation, selective against p21 cell cycle checkpoint-disrupted cells vs. cells with intact p21 checkpoint, were identified by high-throughput screening. Optimization of both ends of the lead molecule to improve potency, using parallel synthesis and iterative design, is described. The 2-(1,4-dibenzodioxane)-substituted derivative 14 was identified as a highly selective and potent agent displaying an IC50 of 91 nM in the p21-deficient cell line.
