The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 2

Abstract

In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and structure–activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H‐bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second‐generation antiviral agents targeting NS5A.

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

“…While HBA counts are high across these molecules (14–18), the number of HBDs is uniform at four, reflective of these as critical elements of the pharmacophore but compliant with the “rule of 5” criterion. Although the carbamate NH elements are not required for potent antiviral activity, they do appear to play a role in membrane permeability, exemplified by studies with the phenylglycine derivative 157 which expresses antiviral potency comparable to that of 147 but is considerably less membrane permeable despite fewer RBs, HBDs, and HBAs and a lower PSA. , Modeling studies have suggested that in environments of low polarity, the carbamate-based compounds like 147 may form an intramolecular H-bond between the imidazole/benzimidazole NH and the carbonyl of the carbamate moiety, structural elements that are a component of all of the compounds compiled in Table . Recalculating the effective 3D-PSA of 147 taking the intramolecular H-bond into account reduces the value to ∼120 Å 2 , closer to the 105 Å 2 calculated for 157 .…”

Determining molecular properties with differential mobility spectrometry and machine learning

“…However, prior to the advent of the EPSA technique, identification of IMHBs, by either computation or experimentation, was challenging 27 . Thus, recent EPSA determinations of IMHB-containing molecules are quickly becoming a gold standard by which to test the ability of DMS to discern such features 31 , 32 .…”

The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex

“…More importantly, target organ exposure was also demonstrated, with liver levels of 103 nM measured in the rat 24 h following a 5 mg/kg dose of 1, a concentration that was fivefold higher than that in plasma. The favorable absorption properties of 1 have been attributed, in part, to the formation of an intramolecular H-bond between the carbamate C¼O and imidazole N-H moieties that enhances lipophilicity and reduces the apparent PSA of the molecule based on a chromatographic analysis and which is supported by modeling studies [41].…”