Katharine A. Grant-Young

4-Thiazolidinones: Novel Inhibitors of the Bacterial Enzyme MurB

4-Thiazolidinones were synthesized and evaluated for their ability to inhibit the bacterial enzyme MurB. Selected 4-thiazolidinones displayed activity against the enzyme in vitro. This activity, coupled with the design principles of the thiazolidinones, supports the postulate that 4-thiazolidinones may be recognized as diphosphate mimics by a biological selector.

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.

Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine.

The anti-influenza activity of a series of thiobenzamide fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine is profiled. Axial disposition of the thioamide moiety is essential for potent influenza inhibitory activity.

Differentially functionalized diamines as novel ligands for the NPY2 receptor

The synthesis of novel ligands for the NPY(2) receptor using solid phase split pool methodology is described. One of the analogues, diamine 16, was found to be a potent NPY(2) binder.

A novel parallel distributor for dispensing of IRORI™ RF‐encoded tags to microkans in 96‐well format

A novel parallel radio-frequency (RF) tag distributor has been developed which allows for distribution of RF tags into Irori microkans in 96-well format. The distributor has a holding capacity of approximately 1000 RF tags and distributes RF tags in groups of 12. Using the distributor, a block of 96 microkans can be filled with RF tags in less than 30 sec resulting in significant time savings over one-at-a-time manual RF tag distribution. The distributor may also be of utility as a solid-phase synthesis tool for dispensing resin enclosed in capsules (which have the same shape as RF tags). Copyright 1998 John Wiley & Sons, Inc.

Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor

Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.