key: cord-0935900-4zxp3uae
authors: Kelley, James L.
title: Chapter 12. Antiviral Agents
date: 1984-12-31
journal: Annual Reports in Medicinal Chemistry
DOI: 10.1016/s0065-7743(08)60688-0
sha: fa30cc76755fb52ffc74b2dfd43497e54a4103cd
doc_id: 935900
cord_uid: 4zxp3uae

Publisher Summary This chapter discusses the agents with activity primarily against RNA viruses. The communicable diseases of the respiratory tract are probably the most common cause of symptomatic human infections. The viruses that are causative agents for human respiratory disease comprise the five taxonomically distinct families: orthomyxoviridae, paramyxoviridae, picornaviridae, coronaviridae, and adenoviridae. The influenza viruses, which consist of types A, B, and C, belong to the family orthomyxoviridae. Types A and B have been associated with significant increases in mortality during epidemics. The disease may be asymptomatic or cause symptoms ranging from the common cold to fatal pneumonia. Immunization against influenza has been recommended for high-risk groups and antiviral chemotherapy (amantadine) is available for the treatment and prophylaxis of all influenza A infections. There is both a great need for and interest in developing a chemotherapeutic agent for the treatment of these two viral, respiratory tract pathogens. The family picornaviridae contains the genus Rhinovirus that is composed of over a hundred distinct serotypes. Amantadine and rimantadine are specifically active against influenza A virus infections. The amantadine recipients reported a higher incidence of side effects largely attributed to the central nervous system (CNS) symptoms. This difference in side effects may be a pharmacokinetic phenomenon that results in higher plasma concentrations of amantadine. Significant progress continues to be made in the clinical use and development of agents active against DNA viruses. Acyclovir (9-(2-h droxyethoxymethyl)guanine) has been the subject of several reviews and of a syrnposium. Considerable progress has been made in evaluating the clinical promise of acyclovir; however, there remains much to be learned concerning the best use of this drug in clinical practice. Significant strides have been made in the development of clinically useful antiviral agents, especially against the DNA viruses of the herpes family. Most of these agents are directed against viral nucleic acid synthesis and require activation by a virus-induced thymidine kinase. Researchers have begun to focus on other strategies that may produce broader spectrum anti-viral agents with different mechanisms of action.

The previous review of antiviral agents in Annual Reports in Medicinal Chemistry emphasized compounds with activity against DNA viruses.' primarily against RNA viruses.

in anti-DNA virus agents is provided. Antiviral agents with activity against RNA viruses were previously reviewed in the 1981 volume.2

Neither interferons nor interferon inducers are included in this review as they were covered in the 1981 and 1982 volumes, respectively. Several reviews have been published that give an overview of the most promising clinical and experimental antiviral agents3-5 or provide background on viral diseases. 6-8 with specific drugs are cited in the sections where these compounds are discussed.

The focus of this year's chapter is on agents with activity A brief update of this year's advances More comprehensive reviews dealing VIRAL RESPIRATORY DISEASE RNA viruses are the major causative factors of the various forms of acute respiratory disease .8 respiratory tract are probably the most common cause of symptomatic human infections. Among both children and adults, acute respiratory tract illness results in significant morbidity, lost time from work, physician visits, and death. It has been calculated that throughout the world over two million deaths occur annually from acute respiratory disease.9 disease comprise the five taxonomically distinct families Orthomyxoviridae, Paramyxoviridae, Picornaviridae, Coronaviridae and Adenoviridae. 9 The influenza viruses, which are comprised of types A, B and C, belong to the family Orthomyxoviridae. Types A and B have been associated with significant increases in mortality during epidemics. The disease may be asymptomatic or cause symptoms ranging from the common cold to fatal pneumonia. Immunization against influenza has been recommended for high-risk groups, and antiviral chemotherapy (amantadine) is available for the treatment and prophylaxis of all influenza A infections. The family Paramyxoviridae includes respiratory syncytial virus (RSV) and parainfluenza virus which are a major cause of lower respiratory tract infections. RSV is a factor in severe bronchiolitis and pneumonia in infants and young children. Efforts to develop a vaccine for RSV have been ineffectual, but recent clinical trials with ribavirin as a small particle aerosol have been promising. The parainfluenza viruses, of which there are four human serotypes, are second only to RSV as a cause of lower respiratory tract illness. There is both a great need for and interest in developing a chemotherapeutic agent for treatment of these two viral, respiratory tract pathogens. The family Picornaviridae contains the genus Rhinovirus, which is composed of over a hundred distinct serotypes. viruses are recognized as the most important causative agents of the upper respiratory tract illness although technical difficulties appear to have hindered studies on vaccines and antiviral agents. The adenoviruses (family Adenoviridae) are a ubiquitous group of doublestranded DNA viruses which are responsible for a wide variety of respiratory illnesses. These infections are most common among children, although acute respiratory disease and pneumonia are also common among military recruits. Two comprehensive reviews of viral respiratory diseases and measures for their control and treatment have been recently published. 8 p 9

The development of a vaccine has been precluded due to 'Coronaviruse (family Coronaviridae) also has an appreciable role in AGENTS ACTIVE PRIMARILY AGAINST RNA VIRUSES Amantadine (l-adamantanamine) and rimantadine (a-methvl-l-adamantanemethvlaminel -Amantadine (1) and rimantadine (2) are specifically active against influenza A virus infections. In 1966 amantadine was licensed for general use against In a large-scale trial, both drugs were highly effective with no significant differences between the rates of illness or infection in the two drug-treated groups. l3 The amantadine recipients reported a higher incidence of side effects largely attributed to central nervous system (CNS) symptoms. l39 l4 effects may be a pharmacokinetic phen menon which results in higher plasma concentrations of amantadine. lg A controlled study of healthy, adult volunteers found 1 and 2 to have minor side effects comparable to those of a common antihistamine. l7 hospital employees receiving amantadine showed a high incidence of CNS symptoms. l8 Guidelines for the use of amantadine in patients with impaired renal function have been formulated from the results of pharmacokinetic studies on amantadine in patients with normal and impaired renal fun~tion.19,~~ Since approximately 90% of an oral dose of amantadine is excreted unchanged in the urine, patients with renal insufficiency can accumulate the drug, resulting in toxic manifestations.

The mechanism by which 1 and 2 inhibit influenza A virus replication had previously been narrowed to a virus-specific event after virus penetration but prior to primary transcription. with radioactive precursors seems to show that uncoating is a multistep process.21 Rimantadine prevents the second step of uncoatin the release of matrix (M) protein from ribonucleoproteins (RNP) .$$ This blocks the penetration of RNP into the nucleus and prevents the nuclear phase of virus reproduction. Amantadine produces the same effect on uncoating as rimantadine.21 These adamantyl amines may also have utility in the treatment of other types of viral infections. been shown to be an effective inhibitor of dengue virus replication & -vitr0.~3 The amelioration of post-herpetic neuralgia due to recurrent herpes simplex sciatica24 and from acute herpes zoster25 has been reported with early administration of amantadine. Ribavirin (l-~-~-ribofuranosyl-1,2,~-triazole-3-carboxamide) -This nucleoside has activity against a broad range of DNA and RNA viruses in An tissue culture and in animal model systems.2 analysis of the status of ribavirin 3) as an is still unresolved but may involve guanosine nucleotides and inhibition of inosine monophosphate dehydrogenase.Z6 In a clinical trial against influenza A, oral ribavirin failed to alter clinical signs and symptoms of the disease.2 However, it OR OR has recently been reported to have a therapeutic effect against both influenza A and influenza B virus infections when administered to patients by inhalation of small-particle aerosol through a face m a s k . 2 7~~~ find utility in those patients at high risk such as the elderly and the chronically ill. Ribavirin has also been shown to inhibit respiratory syncytial virus (RSV) infection in an animal model when administered i.p. or by aerosol treat~nent.~g This in vivo activity has now been substantiated in two controlled, double-blind clinical t r i a l~. 3~, 3~ Administration of a continuous aerosol of ribavirin to infants hospitalized with lower respiratory tract disease from RSV resulted in significant clinical improvement.3 several antiviral agents against Colorado tick fever virus (CTFV), ribavirin inhibited CTFV in vitr0.3~ Ribavirin did not protect mice inoculated intracerebrally with CTFV. However, the 2',3',5'-triacetate derivative 4 significantly increased the number of survivors when administered i.p., which suggests that this lipophilic prodrug of ribavirin is able to crass the blood-brain barrier .32 administration of 2 was also found to protect mice inoculated intracerebrally with dengue virus, under conditions where ribavirin had no significant protective effect.33 In another study, ribavirin reduced the growth of four types of dengue virus in vitro, but it had no effect on virus replication in human peripheral blood leukocytes (PBL) which have been implicated in the pathogenesis of dengue virus in viv0.3~ However, a combination of ribavirin with 6-mercapto-9-(tetrahydro-2furyl)purine, an inhibitor of hypoxanthine-guanine phosphoribosyl transferase, resulted in a marked suppression of dengue virus replication in human PBL.34 

Significant progress continues to be made in the clinical use and development of agents active against DNA viruses. (9-(2-h droxyethoxymethy1)guanine) has been the subject of several r e v i e~s~3 -~~ and of a syrnposium69 during the past year. Clinical trial results have been published that attest to the efficacy of oral acyclovir in the treatment of primary7O and re~urrent7~ genital herpes simplex virus (HSV) infections and in the protection of bone marrow transplant patients from herpes infe~tions.7~ was highly effective in suppressing recurrent herpes sim lex genitalis in a group of patients with unusually frequent episodes.y3 Topical acyclovir cream was effective for treatment of recurrent herpes labiali~.7~ Considerable progress has been made in evaluating the clinical promise of acyclovir; however, there remains much to be learned concerning the best use of this drug in clinical practice.75 Some studies on candidate prodrug forms of acyclovir have recently been published. Several esters of acyclovir were reported to have improved Acyclovir Chronic, oral acyclovir treatment water ~olubility.7~ hydroxyethoxymethyl)purine), which is metabolically deaminated to acyclovir by adenosine deaminase,77 has been reported to be better absorbed from the gut, resulting in higher plasma levels of acycl0vir.7~ Several new reports have further documented the potent antiherpetic activity of 9-(2-hydroxy-l-(hydroxymethyl)ethoxymethyl)guanine. This compound has been reported to be highly effective in reducing the severity of both primary and recurrent lesions of HSV-2 in animal m0dels.79,~~ It also appears to hold substantial promise in the treatment of human cytome alovirus (HCMV) based on its specific anti-HCMV activity & I v i t ro . 8o 9 In an animal model , 9-( 2-hyd roxy-1 -( hydroxyme thy1 ) -ethoxymethy1)guanine was shown to be a potent orally active, chemotherapeutic agent against Equid herpesvirus .82 l-6-D-arabinofuranosylcytosine) has been reported to stabilize cutaneous lesions in immunosuppressed patients suffering from acute herpesvirus infection.84 A minor metabolite of FIAC, 2'-fluoro-5-methyl-l-f3-~arabinofuranosyluracil (FMAU), is also antiherpetic, but, in addition, it has i.p. and p.0. activity against murine leukemias resistant to 1-6-garabinofuranosylcytosine. Pharmacokinetic studies on FIAC and FMAU have been p~blished,~5 and the synthesis and & itro anti-HSV antiviral activity of BVDU ((E)-5-(2-bromovinyl)-2'-deoxyuridine) and other 5-substituted pyrimidine nucleoside analogs has been published ,87 Several 2',3'-diester and 5'-monoester prodrug forms of ara-A (9-(l-B-Q-arabinofuranosyl)adenine) have been evaluated with favorable results in HSV-2 induced genital infections in female guinea pigs. 88 The 5'-monophosphate of ara-A was found to be as effective as ara-A in the treatment of immunosuppressed patients suffering from varicella-zoster .89 A carbocyclic analog of ara-A, cyclaradine, and its 5'-methoxyacetate ester have been reported to have activity in an HSV-1 encephalitis animal model that was comparable to the activity demonstrated by ara-A.gO These two compounds may possess some clinical advantage over ara-A due to their low systemic toxicity. acid (PFA, foscarnet sodium), which is presently in Phase 111 clinical trials in Eur0pe,~3 have been discussed in a recent re~iew.9~ synthesis and structural requirements for antiherpes activity of a series of PFA esters have also been rep0rted.9~ A diaminopurine analog A134U (2,6-diamino-9-(2-FIAC (2'-fluoro-5-iodoactivities of a series of analogs have been reported. k A review of the The antiviral effects of phosphonoformic The APPROACHES TO THE DESIGN OF ANTIVIRAL AGENTS Significant strides have been made in the development of clinically useful antiviral agents, especially against the DNA viruses of the herpes family. Most of these agents are directed against viral nucleic acid synthesis and require activation by a virus-induced thymidine kinase. Researchers are beginning to focus on other strategies which may produce broader spectrum antiviral agents with different mechanisms of action. Inhibition of polyamine biosynthesis may serve as a suitable target for antiviral drug design. bis(guany1hydrazone) and u-difluoromethylornithine, an inhibitor of polyamine biosynthesis have recently been reported to inhibit replication of human CMV in vitro.43 methylation reactions. For some viruses, efficient replication is dependent on viral mRNA that has been methylated at its 5I-terminal guanosine residue. effective inhibitor of this cappin mRNA( g~anine-'7-)methyltransferase.~~ Another permutation of this theme is preservation of cellular S-adenosylhomocysteine (SAH) by inhibition of SAH hydrolase. SAH is an endogenous inhibitor of transmethylation The polyamine antimetabolite methylglyoxal Another target is the inhibition of essential Ribavirin 5'-triphosphate has been reported to be an reaction which is catalyzed by a reactions in which S-adenosylmethionine is the methyl donor .95 system i effe~t.9~997 There has been substantial interest in exploiting this system as an approach to antiviral drug development. primarily been aimed at the synthesis of 2-5A core analogs that are permeable to cells and stable to degradative enzymes. During the process of infection some viruses change the permeability of infected cells. This allows cellular penetration by compounds that are normally excluded.

The selective antiviral activity of hygromycin B supports the suggestion that screening for agents which are selectively permeable to virus infected cells could result in broad-spectrum antiviral agents .g8 A review of the concept of selective delivery of antiviral agents by con jugation with protein carriers has been published. 99 This activity appears to be mediated by an obligatory lysosomal step in the uncoating of enveloped viruses. Amines such as chloroquine may prevent uncoating by increasing the lysosomal pH above a value required for release of the virus nucleocapsid into the cytoplasm. A better understanding of this process could lead to the development of broad-spectrum antiviral agents.

The 2-5A one of the mechanisms by which interferon exerts its antiviral These efforts have 

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