Robert P. Farrell

Novel antineoplastic agents with efficacy against multidrug resistant tumor cells

A novel series of pentafluorobenzenesulfonamides has been shown to inhibit the growth of a variety of human tumor cell lines. Among the cell types against which these agents were evaluated were the multidrug resistant (MDR) cell lines MCF-7/ADR and P388/ADR. The cytotoxic activity of members of this series of compounds was not affected by the multidrug resistant pump in MCF-7/ADR or P388/ADR cells.

Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure―activity relationships of benzothiazine-substituted quinolinediones

A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.

Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides

A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.

Alkoxy substituted benzisothiazolone (BIT) derivatives: potent inhibitors of human leukocyte elastase

Abstract Alkoxy substituted benzisothiazolones (BIT) are reported as inhibitors of human leukocyte elastase (HLE). Structure-activity relationship study results are described. The contribution of alkoxy substituents towards improving the stability of BIT derivatives in human blood is discussed. WIN 68769 ( 12 ) with a Ki ∗ = 0.022 nM is the most potent analog synthesized in this series.

A CONVENIENT SYNTHESIS OF PHENOXY CARBOXAMIDES FROM PHENOLS USING THE MITSUNOBU REACTION

Abstract An efficient method for the direct conversion of phenols to phenoxy carboxamides is presented. This synthetic methodology is utilized to produce potent human leukocyte elastase inhibitors.