A recent letter in ACS Med.Chem.Lett. details the optimisation of a series of inhibitors of the Hepatitis C virus (HCV) NS3/4A protease, and is interesting in that it provides detailed pharmacokinetic data for a series of macrocyclic lactones, a class of therapeutic agents with physicochemical properties that fall outside the typical range with which most medicinal chemists are familiar.
The current front line therapy for HCV infection (which can lead to liver cirrhosis) involves treatment with PEGylated interferon α (PEGasys or PEG-Intron, by injection) and ribavirin (orally). Unfortunately this approach has limited efficacy due, in part, to the low completion rates observed for the lengthy (~1 year) course of therapy. The clear need for improved therapies and the associated commercial opportunity has led to many companies progressing molecules into the clinic (see this overview of the area), a number of which have targeted NS3/4A protease. The NS3/4A protease represents an attractive target as it is essential for viral polyprotein maturation. Boehringer Ingelheim (BI) initially led the field in this area and achieved proof of concept with BILN-2061, although this molecule was subsequently terminated due to cardiac toxicity in pre-clinical species. More recently, both Vertex (Telaprevir, VX-950) and Schering-Plough (Boceprevir, SCH 503034) have advanced molecules to Phase III, with several other companies close behind.
A previous report from Merck had described their entry into this field using a molecular modelling approach to design analogues of BILN-2061. Interestingly, this approach led to the surprisingly straightforward switch from a P1-P3 tether (highlighted above) to a P2-P4 tether (see below) and subsequently to the identification of a clinical candidate, MK-7009, following painstaking optimisation of the P2 and P3 substituents.
This highly potent candidate intriguingly contains 2 carbamate groups within its macrocyle. Good plasma exposures were observed in dogs and chimpanzees and whilst high liver exposures (which is clearly key for the target indication) were obtained in rats and rhesus monkeys, disappointingly low plasma exposures (which are required to access the non-hepatic HCV replication sites) were observed in these species.
In an effort to address these potential shortcomings, the letter describes the optimisation of the isoquinoline template, originally reported in the J.Am.Chem.Soc. paper referenced above, rather than the isoindoline carbamate present in the first clinical candidate (MK-7009). The authors describe how they sought to improve the potency and rat plasma/liver concentrations, relative to their previous lead molecule, mainly by changes to the P3 group and to the isoquinoline substituents. Unfortunately, and the authors are to be admired for their refreshing honesty in this respect, the PK of this series was unpredictable and there was no alternative but to screen a large number of compounds to identify those which combined the highest rat oral plasma and liver exposures with the requisite potency. A seemingly clear link was observed between increased lipophilicity at P3 and both an increase in plasma concentrations and a reduction in potency in the serum protein-containing assay system that was used. However, this understandable link to lipophilicity did not hold for all changes or indeed for all of the isoquinoline substituents that were explored. In the end, it appears that the clinical candidate, MK-1220, was chosen following the detailed characterisation of a relatively large set of similar analogues.
Nonetheless, these data do provide the opportunity to reflect on the fact that some of these macrocyclic templates are able to achieve good levels of cell permeability and display favourable pharmacokinetic profiles whilst clearly lying in an increasingly taboo physicochemical and molecular weight territory (a recent paper from Ensemble Therapeutics Corp. gives some further insight into this area of drug discovery in which the rule of five is clearly violated).