Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.

The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week.

Pyrrolidine-5,5-trans-lactams. 5. Pharmacokinetic optimization of inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.

Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.

The design of potent, non-peptidic inhibitors of hepatitis C protease.

The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.

Design and synthesis of spiro-cyclopentenyl and spiro-[1,3]-dithiolanyl substituted pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease.

Using the pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 2b, with a spiro-cyclobutyl P1 substituent and an isopropyl carbonyl substituent at the lactam nitrogen, has an IC(50) value in the replicon cell-based assay of 3 microM.

Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents.

[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.

Pyrrolidine-5,5-trans-lactams. 1. Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g.

Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease.

Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.