An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus

Abstract

Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus−compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.

Identification of a Series of Compounds with Potent Antiviral Activity for the Treatment of Enterovirus Infections

“…These include Rupintrivir, 5 a viral 3C protease inhibitor, and a number of compounds that prevent virus entry into cells by binding to the viral capsid: Pirodavir, 6 Pleconaril, 7 and BTA798. 8 Only the latter of these is currently in clinical development, the others having been terminated due to lack of clinical efficacy or unacceptable side effects.As part of an antiviral program directed toward hepatitis C (HCV), we identified a series of imidazo-pyrazines with modest (micromolar) activity in a genotype 1b replicon screen ( Figure 1). These compounds were derived from a BioFocus SoftFocus library (SFK28) initially designed as potential kinase inhibitors.…”

Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket

“…All high-level resistance (HR) ) to CIs reported to date involve residues forming the hydrophobic pocket of EVEVs Benschop et al, 2015;Groarke and Pevear, 1999;Ledford et al, 2005;Ledford et al, 2004;Schmidtke et al, 2005) Benschop et al, 2015;Groarke and Pevear, 1999;Ledford et al, 2005;Ledford et al, 2004;Schmidtke et al, 2005), hence directly interfering with the binding of CIs. Because of similarities in the binding mode of CIs, cross-resistance may be observed, as reported for pleconaril and vapendavir (Feil et al, 2012) (Feil et al, 2012).…”

“…All high-level resistance to CIs reported to date involve residues forming the hydrophobic pocket of EVs Benschop et al, 2015;Groarke and Pevear, 1999;Ledford et al, 2005;Ledford et al, 2004;Schmidtke et al, 2005), hence directly interfering with the binding of CIs. Because 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 of similarities in the binding mode of CIs, cross-resistance may be observed, as reported for pleconaril and vapendavir (Feil et al, 2012).…”

“…Several capsid-binding inhibitorsmolecules (CIs) are being investigated as promising drug candidates (Andries et al, 1991;Diana, 2003;Makarov et al, 2005;Watson et al, 2003) (Andries et al, 1991;Diana, 2003;Makarov et al, 2005;Watson et al, 2003), the most developed ones being pleconaril and vapendavir (Diana et al, 1995;Feil et al, 2012) (Diana et al, 1995;Feil et al, 2012).…”

“…As of today no therapeutics have been approved for the treatment of these infections (De Palma et al, 2008;Rollinger and Schmidtke, 2011). Several capsid-binding molecules (CIs) are being investigated as promising drug candidates (Andries et al, 1991;Diana, 2003;Makarov et al, 2005;Watson et al, 2003), the most developed ones being pleconaril and vapendavir (Diana et al, 1995;Feil et al, 2012).…”