Presentation on theme: "Sept 21, 2006 SMALL MOLECULE INHIBITORS OF ANTHRAX LETHAL FACTOR Phase I SBIR Project Period 7/01/05-6/30/07 P.I. Norton Peet John D. Williams."— Presentation transcript:
Sept 21, 2006 SMALL MOLECULE INHIBITORS OF ANTHRAX LETHAL FACTOR Phase I SBIR Project Period 7/01/05-6/30/07 P.I. Norton Peet John D. Williams
Sept 21, 2006 SPECIFIC AIMS 1.Optimize the in vitro LF inhibitory activity of the validated hit series a)Lead compound SAR b)Modeling/X-ray crystallography c)Biochemical activity against LF—Fluorescence-based/HPLC d)Continued screening of the MBX compound library against LF 2.Demonstrate potent selective inhibitory activity in cellular models of LF action a)Medicinal chemistry b)Cellular protection and toxicity assays 3.Identify LF inhibitors with in vitro ADME properties suitable for oral dosing 4.Identify lead LF inhibitors that are active in an in vivo model
Sept 21, 2006 LF Inhibitor NSC 12155 Compound NSC 12155 emerged as a lead compound with: –K i of 0.5 M in the LF assay –EC 50 < 25 M in a cell-based assay. NSC 12155 has also been used as a starting point for the SAR studies.
Sept 21, 2006 SAR: General Trends Simple aromatic compounds inactive Polyaromatics generally more active Tether of ~4 atoms seems to have highest activity Phenylpropionamides need 2-substituent Cinnanamides have lower requirements, lower activity
Sept 21, 2006 SAR: What Next? Inhibitor-Bound X-Ray structure may provide more ideas and/or refinements