Imidazo[1,2-<i>b</i>]pyridazines, Novel Nucleus with Potent and Broad Spectrum Activity against Human Picornaviruses:  Design, Synthesis, and Biological Evaluation

Hamdouchi, Chafiq; Sanchez-Martinez, Concha; Gruber, Joseph M.; Prado, Miriam Del; Lopez, Javier; Rubio, and Almudena; Heinz, Beverly A.

doi:10.1021/jm020583i

Cited by 35 publications

(25 citation statements)

References 12 publications

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“…This series was shown to have significant improvement in potency relative to the imidazo[1,2-a]pyridines series, but did not lead to the discovery of more potent enviroxime analogues. 215 Preliminary experiments by Ninomiya et al 216 suggested that enviroxime acts at the level of viral RNA replication. Subsequent studies confirmed indeed that enviroxime inhibits the initiation of plus-strand RNA synthesis by targeting the 3A protein; however, the exact molecular mechanisms regarding this inhibition remained unclear.…”

Section: E Enviroxime and Analoguesmentioning

confidence: 99%

Selective inhibitors of picornavirus replication

Palma

Vliegen

Clercq

et al. 2008

Medicinal Research Reviews

229

217

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Picornaviruses cover a large family of pathogens that have a major impact on human but also on veterinary health. Although most infections in man subside mildly or asymptomatically, picornaviruses can also be responsible for severe, potentially life-threatening disease. To date, no therapy has been approved for the treatment of picornavirus infections. However, efforts to develop an antiviral that is effective in treating picornavirus-associated diseases are ongoing. In 2007, Schering-Plough, under license of ViroPharma, completed a phase II clinical trial with Pleconaril, a drug that was originally rejected by the FDA after a New Drug Application in 2001. Rupintrivir, a rhinovirus protease inhibitor developed at Pfizer, reached clinical trials but was recently halted from further development. Finally, Biota's HRV drug BTA-798 is scheduled for phase II trials in 2008. Several key steps in the picornaviral replication cycle, involving structural as well as non-structural proteins, have been identified as valuable targets for inhibition. The current review aims to highlight the most important developments during the past decades in the search for antivirals against picornaviruses.

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Section: E Enviroxime and Analoguesmentioning

confidence: 99%

Selective inhibitors of picornavirus replication

Palma

Vliegen

Clercq

et al. 2008

Medicinal Research Reviews

229

217

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“…A novel structural class of inhibitors, the imidazo[1,2-b]pyridazine derivatives, displayed potent and broad spectrum activity against human picornaviruses. For example, the oxime derivative (E)-109 potently inhibited several human rhinoviruses (HRV14, HRV2 and HRV16), poliovirus-1, coxsackieviruses (A21 and B3) with an average IC 50 of 0.04 μg/mL [291].…”

Section: Clan Pa(c) Family C3: Human Rhinovirus 3c Protease or Hrv-3mentioning

confidence: 99%

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Leung-Toung

Zhao²,

Li³

et al. 2006

CMC

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A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.

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“…Thus, a series of imidazo [1,2-b]pyridazines based on the structure of enviroxime were synthesized, designed to have similarly potent broad-spectrum anti-picornavirus activity and better oral bioavailability [41]. The oxime derivative, 2-amino-3-(4-fluorophenyl)-6-benzoylimidazo [1,2] pyridazine oxime, was the most potent inhibitor of HRV14 (IC50 = 0.05 µg/ml).…”

Section: Viral Rna Synthesis Inhibitorsmentioning

confidence: 99%

Current Status of Anti-Picornavirus Therapies

Barnard

2006

CPD

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Picornaviruses are important human pathogens causing severe morbidity and some mortality with the potential to cause worldwide crippling disease. Currently, there are few treatments for many of the viruses in the Picornaviridae, For rhinoviruses, there are no approved treatments, although ruprintrivir looks promising in clinical trials and pyridazinyl oxime ethers may prove useful. Poliovirus treatments are needed to supplement the World Health Organization's polio eradication plan in order to treat infections caused by reversion of the attenuated vaccine virus and to supplement vaccine coverage control in polio endemic areas. However, no promising compounds for treatment of poliovirus have been developed due to the efficacy of the vaccines in use. Broad-spectrum inhibitors developed for other picornavirus may be useful for poliovirus infections. Coxsackievirus infections in children and in infants are being treated with pleconaril with some efficacy in reducing mortality and improving recovery, albeit the treatment is often on a compassionate use basis. There are no therapies for echovirus infections. Very little drug discovery research is being done to develop inhibitors for echovirus infections, probably due to the broad-spectrum inhibition exhibited by capsid binding agents and protease inhibitors discovered for treatment of other picornaviruses. For example, pyridazinyl oxime ethers are inhibitory to most echoviruses. Treatments for enterovirus infections are also limited, although in a small clinical trial, milrinone seemed to reduce mortality and improve recovery from EV71-induced pulmonary edema. Thus, these results strongly emphasize the need for the development of potent and nontoxic compounds for the treatment of picornavirus infections.

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Imidazo[1,2-b]pyridazines, Novel Nucleus with Potent and Broad Spectrum Activity against Human Picornaviruses: Design, Synthesis, and Biological Evaluation

Cited by 35 publications

References 12 publications

Selective inhibitors of picornavirus replication

Selective inhibitors of picornavirus replication

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Current Status of Anti-Picornavirus Therapies

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