Thomas William Hudyma

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Chapter 18. Non-steroidal Antiinflammatory Agents

Publisher Summary This chapter highlights the research in the area of nonsteroidal antiinflammatory agents (NAA) with an emphasis on work relating to the chronic arthritic diseases. There have been few notable developments in the past in in vivo methods used to screen for and evaluate NAA. Increasing reliance is being placed upon the adjuvant-induced arthritis assay in the rat because it is felt that the histochemistry and pathology of this autoimmune disease most closely resemble the histochemistry and pathology of some of the human arthritic diseases. An improved quantitative method that employs the dog has been reported in which the pressure exerted by the dog paw is measured after injection of an inflammatory agent into the corresponding knee joint. In another study, intrazole (BL-R743), aspirin, and phenylbutazone effectively inhibited rabbit platelet aggregation in both in vitro and in vivo screens. Aspirin and other NAA inhibited human blood platelet aggregation. In all these cases, the compounds were considered to work by inhibiting the release mechanism.