pwkenny

Hi @edgriffen @mc-robinson

I would question the tactic of increasing volume of distribution in order to decrease clearance. A reduction in clearance resulting from increased volume of distribution (or increased plasma protein binding) is due to a greater proportion of the dose being hidden from the metabolic enzymes. If you hide the drug from the metabolic enzymes then you’ll also hide it from the target. If the volume of distribution is large, it’ll take more than a single dose to get to therapeutic concentration (might be able to use a loading dose).

I think that you’ll be asking for trouble by introducing a basic center that is not needed for binding to target. If the basic center is predominantly protonated at neutral pH, you’ll run the risk of cation problems like hERG etc. If the basic center is predominantly unprotonated at neutral pH, you probably won’t get the increase in volume of distribution that you’re looking for. My understanding is that Mpro is in a neutral compartment and an inhibitor with a basic center is likely to concentrate in acidic compartments like lysosomes (where it will be presented to other proteases that may be anti-targets).

edgriffen

Sorry for the delay in replying Pete - all valid points, it’s not my preferred strategy to add a basic centre, but there is Glu 166 in the neighbourhood, 5/6 of the compounds we’ve tested to date aren’t taking much of a hit. SPeaking to your concerns about tox - hence our extensive focus on keeping the pKa relatively low to avoid ion channels and hopefully CNS effects. Getting the Vd to 2 would probably be enough if the clearance stays the same. It’s one of a number of tactics - all eggs are not in this basket.