Thomas W Hudyma

Learn More
Hepatitis C virus (HCV) RNA-dependent RNA polymerase (NS5B) is required for viral replication. Crystal structures of the NS5B apoprotein show that the finger and thumb domains interact to encircle the active site, and that inhibitors defined by P495 resistance that bind to the thumb-finger interface displace the Δ1 finger loop and disrupt this structure.(More)
Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and(More)
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)(More)
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic(More)
The synthesis of some 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acids and esters with potent oral and intravenous antiallergic activity against passive cutaneous anaphylaxis in the rat is described. Requirements for high activity include a free NH group in the pyrimidinone nucleus and a small to medium size ortho alkoxy or alkenyloxy group on the(More)
Presented here are initial structure-activity relationship (SAR) studies on a series of novel heteroaryl fused tetracyclic indole-based inhibitors of the hepatitis C viral polymerase, NS5B. The introduction of alternative heterocyclic moieties into the indolo-fused inhibitor class significantly expands the reported SAR and resulted in the identification of(More)