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  • A series of P P ureas were explored


    A series of P3-P4 ureas were explored first and their anti-NS3 protease activity, antiviral properties in a HCV replicon cell-based assay and PK profiles examined. Installation of a methyl group on the P4 side nitrogen A-1210477 of the urea yielded , a molecule which retained intrinsic potency against the GT 1a NS3 protease but exhibited reduced potency in the GT 1b replicon cell-based assay when compared to the parent urea analogue . Transposition of the methyl group to the P3 side of the urea provided , a compound with poor potency in the biochemical assay. While this result appeared discouraging with respect to the hypothesis under examination, a model of bound to the NS3/4a protease complex suggested that steric repulsion between the urea methyl substituent and the P3 -butyl moiety may result in a local conformation in which hydrogen-bonding between the remaining urea N–H and the carbonyl of Ala-157 was unfavorable. In order to probe relief of this potential source of steric strain in , replacement of the P3 -butyl with the corresponding -butyl group was examined. This subtle but important structural modification restored inhibitory properties against the enzyme, as exemplified by compounds and . Compounds , and offered comparable performance in the rat PK screen but each demonstrated significantly enhanced (17 to 36-fold) liver levels when compared to the parent urea . However, plasma levels for these compounds remained relatively low and this series was not progressed. In an effort to further the observation that the hydrogen-bond donor could reside on either side of the P4 carbonyl oxygen atom, we next considered a series of reverse carbamates in the context of – since the oxygen atom would present a sterically relatively undemanding element at this site of the pharmacophore. Modeling of carbamate and reverse carbamate with the NS3/4a protease complex illustrated the similarity of the hydrogen-bond distances between the carbamoyl NH of the two compounds and the backbone carbonyl of Ala-157 (). The observed improvement in potency against the NS3 protease with reverse carbamates – was notable, just 3-fold less than the parent carbamate . However, the PK profile of compounds – after ID dosing was similar to the parent series and hence reverse carbamates appeared to offer no advantage over the parent series represented by . It should be noted that the use of a reverse carbamate functionality at the P3-P4 position of inhibitors of serine protease has found somewhat limited application. However, the activity observed with this functionality in the current series suggests that reverse carbamates may be a viable replacement for -terminal amide or carbamate capping groups. In summary, we have described the design of a series of P3-P4 urea-linked compounds that provided significant intrinsic antiviral potency as well as aqueous solubility advantages over P3-P4 carbamate-linked tripeptide HCV NS3 protease inhibitors. The lipophilic P4 structural component of these inhibitors was adjusted to provide for optimal potency. The concept of hydrogen-bond donor transposition at the P3-P4 junction was successfully demonstrated with both -methylated ureas and reverse carbamates. Despite several advantages discovered with the P3-P4 ureas, these derivatives were characterized by permeability and exposure shortcomings, presumably due to the inherent polarity of the urea motif itself. A strategy to overcome these shortcomings was implemented with moderate success but, ultimately, the PK profiles of the P3-P4 urea compounds did not yield the targeted PK parameters, leading to this series being dropped from further consideration.
    Introduction Hepatitis C virus (HCV) is a global threat infecting 75 million people worldwide (Blach et al., 2017). Over 80% of individuals nfected with HCV develop chronic liver disease, which often progresses to cirrhosis or becomes malignantly transformed to hepatocellular carcinoma. Prior to the introduction of direct-acting antivirals (DAAs), the standard of care for HCV infection consisted of pegylated interferon-α and ribavirin (Ghany et al., 2011). This treatment resulted in a sustained virological response (SVR; the standard indication of cure from infection) of less than 50% against genotype 1 (GT1) and had low tolerability due to severe side effects (Fried et al., 2002). Fortunately, in the last several years the advent of DAAs against essential viral proteins NS3/4A, NS5A, and NS5B has significantly improved therapeutic options and treatment outcomes for patients infected with HCV (Asselah et al., 2016, Falade-Nwulia et al., 2017).