Intranasal pirodavir (R77,975) treatment of rhinovirus colds

Hayden, Frederick G.; Hipskind, Gloria; Woerner, Diane; Eisen, Glen; Janssens, Michel; Janssen, P. A. J.; Andries, Koen

doi:10.1128/aac.39.2.290

Cited by 99 publications

(54 citation statements)

References 10 publications

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“…14 While effective in experimental challenge studies when administered very frequently intranasally, 15,16 the ester functionality of pirodavir 2 has been shown to undergo facile hydrolysis in vivo to the carboxylic acid, which is inactive, 17 and this ease of hydrolysis renders the molecule unsuitable for oral administration.…”

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confidence: 99%

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

Feil

Hamilton²,

Krippner³

et al. 2012

ACS Med. Chem. Lett.

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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.

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confidence: 99%

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

Feil

Hamilton²,

Krippner³

et al. 2012

ACS Med. Chem. Lett.

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“…The HEV include over 70 viruses that are associated with diverse clinical syndromes ranging from mild, self-limiting infections to fulminant and potentially fatal disease (3,52,53). Earlier clinical studies with agents that inhibit virus attachment and/or uncoating (e.g., tremacamra, a soluble intracellular adhesion molecule-1, pirodavir, and pleconaril) and nonspecific antiviral agents such as ␣-2␤ interferon have demonstrated that prevention and early treatment of HRV colds could provide clinical benefit (3,(18)(19)(20)(21)(22)(23)53). Recently, a retrospective analysis of two multicenter clinical trials demonstrated that pleconaril, a capsid-function inhibitor (17), significantly reduced the duration and severity of picornavirus-induced colds (24).…”

mentioning

confidence: 99%

Conservation of Amino Acids in Human Rhinovirus 3C Protease Correlates with Broad-Spectrum Antiviral Activity of Rupintrivir, a Novel Human Rhinovirus 3C Protease Inhibitor

Binford

Maldonado

Weady

et al. 2005

Antimicrob Agents Chemother

142

116

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The picornavirus 3C protease is required for the majority of proteolytic cleavages that occur during the viral life cycle. Comparisons of published amino acid sequences from 6 human rhinoviruses (HRV) and 20 human enteroviruses (HEV) show considerable variability in the 3C protease-coding region but strict conservation of the catalytic triad residues. Rupintrivir (formerly AG7088) is an irreversible inhibitor of HRV 3C protease with potent in vitro activity against all HRV serotypes (48 of 48), HEV strains (4 of 4), and untyped HRV field isolates (46 of 46) tested. To better understand the relationship between in vitro antiviral activity and 3C protease-rupintrivir binding interactions, we performed nucleotide sequence analyses on an additional 21 HRV serotypes and 11 HRV clinical isolates. Antiviral activity was also determined for 23 HRV clinical isolates and four additional HEV strains. Sequence comparison of 3C proteases (n ‫؍‬ 58) show that 13 and 11 of the 14 amino acids that are involved in side chain interactions with rupintrivir are strictly conserved among HRV and HEV, respectively. These sequence analyses are consistent with the comparable in vitro antiviral potencies of rupintrivir against all HRV serotypes, HRV isolates, and HEV strains tested (50% effective concentration range, 3 to 183 nM; n ‫؍‬ 125). In summary, the conservation of critical amino acid residues in 3C protease and the observation of potent, broad-spectrum antipicornavirus activity of rupintrivir highlight the advantages of 3C protease as an antiviral target.The picornavirus family consists of over 200 medically important viruses, including human rhinoviruses (HRV) and human enteroviruses (HEV). HRV, comprising over 100 different serotypes, are a major cause of mild upper respiratory infections (reviewed in references 4, 8, and 40). Although HRV infections are usually mild and self-limiting, they can also be associated with exacerbation of disease in individuals with underlying respiratory disorders (4, 48). The HEV include over 70 viruses that are associated with diverse clinical syndromes ranging from mild, self-limiting infections to fulminant and potentially fatal disease (3,52,53). Earlier clinical studies with agents that inhibit virus attachment and/or uncoating (e.g., tremacamra, a soluble intracellular adhesion molecule-1, pirodavir, and pleconaril) and nonspecific antiviral agents such as ␣-2␤ interferon have demonstrated that prevention and early treatment of HRV colds could provide clinical benefit (3, 18-23, 53). Recently, a retrospective analysis of two multicenter clinical trials demonstrated that pleconaril, a capsid-function inhibitor (17), significantly reduced the duration and severity of picornavirus-induced colds (24). To date, however, no antiviral agents have been approved for the prevention or treatment of HRV infection.We have focused our antiviral strategy on the inhibition of 3C protease, a viral enzyme that is absolutely required for the proteolytic cleavage of viral precursor polyproteins to functional p...

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“…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.…”

mentioning

confidence: 99%

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

MacLeod¹,

Mitchell²,

Palmer³

et al. 2013

ACS Med. Chem. Lett.

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Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition. KEYWORDS: antiviral, enterovirus, HCV, inhibitor, PI4KIIIβ O ver the last 15 years, evidence has gathered that viral infections of the respiratory tract are a major cause of exacerbations in both chronic obstructive pulmonary disease (COPD) 1 and asthma. 2 Of these infections, half to two-thirds are caused by human rhinovirus (HRV), the most well-known etiologic agent of the common cold.3 While these infections are merely inconvenient in otherwise healthy individuals, exacerbation of the symptoms of COPD and asthma are serious, leading to very large numbers of hospitalizations and significant mortality. In fact, the prevalence of COPD is increasing rapidly, and it is predicted to become the third leading cause of death globally by 2030. 4 Hence, the identification of compounds that can interfere with rhinovirus replication may lead to drugs that have important clinical value in the management of a growing medical need.In the past, several drug candidates have been progressed into clinical trials for the treatment of HRV 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.Additional screening of the imidazo-pyrazines against a panel of other viruses revealed similar activity against the Enteroviruses, a genus of the Picornaviridae family, including HRV, polio virus (PV), and Coxsackie virus (CV). In most cases, the compounds were 3−5-fold more active against enteroviruses, which, in common with HCV, are positive-sense singlestranded RNA (+ssRNA) viruses. The compounds proved inactive against other RNA, DNA, and retroviruses and were not cytotoxic at antiviral concentrations, indicating a specific and selective antiviral effect.Enteroviruses present a range of threats to human health, from the common cold ...

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Intranasal pirodavir (R77,975) treatment of rhinovirus colds

Cited by 99 publications

References 10 publications

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

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

Conservation of Amino Acids in Human Rhinovirus 3C Protease Correlates with Broad-Spectrum Antiviral Activity of Rupintrivir, a Novel Human Rhinovirus 3C Protease Inhibitor

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

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