Respiratory syncytial virus fusion inhibitors. Part 7: structure-activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo.

A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure-activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic substituents that established good potency for the series.

Respiratory syncytial virus fusion inhibitors. Part 6: an examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety.

The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors 4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (1).

Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.

A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration.

Respiratory syncytial virus fusion inhibitors. Part 3: Water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo.

The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration.

Respiratory syncytial virus inhibitors. Part 2: Benzimidazol-2-one derivatives.

Structure-activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of benzotriazole derivatives on which 2 is based, and revealed a broad tolerance for substituent size and functionality.

Orally active fusion inhibitor of respiratory syncytial virus.

BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation.

Salicylamide inhibitors of influenza virus fusion.

Structural variation of the quinolizidine heterocycle of the influenza fusion inhibitor BMY-27709 was examined by several topological dissections in order to illuminate the critical features of the ring system. This exercise resulted in the identification of a series of synthetically more accessible decahydroquinolines that retained the structural elements of BMY-27709 important for antiviral activity. The 2-methyl-cis-decahydroquinoline 6f was the most potent influenza inhibitor identified that demonstrated an EC50 of 90 ng/mL in a plaque reduction assay.

1,2-Benzisothiazol-3-one 1,1-dioxide inhibitors of human mast cell tryptase.

A library of compounds were prepared by reacting 2-(bromomethyl)-1, 2-benzisothiazol-3(2H)-one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1, 2-benzisothiazol-2(3H)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 microM).

Salutaridine N-Oxide from the Capsules of Papaver bracteatum.

A novel compound, salutaridine N-oxide ( 1) has been isolated from PAPAVER BRACTEATUM Lindl (Papaveraceae) in which the major alkaloids were salutaridine and thebaine. Semisynthetic 1 was prepared for structure confirmation. Other components of the alkaloidal fraction were isothebaine, oripavine, neopine, and thebaine N-oxide.