Macromolecular neuraminidase-binding compounds

Details Macromolecular neuraminidase-binding compounds Macromolecular neuraminidase-binding compounds

1999-07-16

2004-01-20

Wortman, Donna C. (Department: 1648)

Drug, bio-affecting and body treating compositions

Conjugate or complex of monoclonal or polyclonal antibody,...

Conjugated via claimed linking group, bond, chelating agent,...

C435S005000, C514S459000, C530S402000

Reexamination Certificate

active

06680054

ABSTRACT:

This invention relates to a new class of chemical compounds and their use in medicine. In particular the invention provides novel macromolecules, methods for their preparation, pharmaceutical formulations thereof and their use as anti-influenza agents. The invention also provides a novel diagnostic method which can be used for detection of all types of influenza A and B virus.
BACKGROUND OF THE INVENTION
Influenza A and B viruses are major causes of acute respiratory disease, resulting in an estimated 30-50 million infections annually in the United States alone. Influenza A has been responsible for major epidemics, such as the “Spanish Flu” of 1919 which killed millions of people. Influenza remains a difficult disease to control, resulting in significant morbidity, and mortality largely due to secondary infection in eldery or debilitated patients. Vaccines are continually being rendered obsolete by antigenic shift or drift, and consequently immunization is only about 70% effective in preventing infection. The only drugs approved by regulatory authorities for treatment of influenza are amantidine and rimantidine, which are ineffective against influenza B, and are known to have serious side-effects.
Many viral and bacterial infections may present with symptoms similar to those of influenza. The rapid identification of respiratory viruses would enable physicians to use the most appropriate therapy early in the illness. For example, an early and accurate diagnosis would allow decisions regarding the use of antibacterial therapy and hospitalisation of children and the elderly.
Laboratory tests for the identification of viruses in clinical material are widely used, and a variety of different detection methodology is available. The textbook, “Laboratory Diagnosis of Viral Infections”, Marcel Dekker 1992, Ed E. H. Lennette generally discusses methods which are used for a wide range of viruses, including influenza virus.
A number of tests are available for the diagnosis of influenza A and B. The traditional method of identifying influenza viruses has been the use of cell culture, which is highly sensitive and specific. Unfortunately, the time required for culture, isolation and identification of influenza virus can range between 2 and 10 days, thus making it virtually useless in guiding the physician to an appropriate therapy. Since influenza virus infection is normally self-limited, diagnosis must be rapid if therapy is to be effective.
In addition to the cell culture methods for detecting influenza, there have recently become available a few rapid direct tests, which are specific for influenza A. Thus, a monoclonal immunofluorescence assay (IFA) has been reported (Spada, B. et al, J. Virol. Method, 1991 33 305) and at least one rapid enzyme immunoassay (EIA) is available (Ryan-Poirier, K. A. et al, J. Clin. Microbiol., 1992 30 1072). A number of comparisons of these rapid detection methods for influenza A have been reported; see for example Leonardi, G. P. et al, J. Clin. Microbiol., 1994 32 70, who recommended that direct specimen testing be used together with culture isolation, so as to permit both identification of the virus in time to institute therapy and infection control measures, and to monitor the antigenic constitution of influenza strains prevalent in the community.
The IFA method is reported to be labor-intensive, and requires considerable technical expertise, with the results often being difficult to interpret. On the other hand, the EIA (Directigen FLU-A; Becton Dickinson Microbiology Systems) method gave a high level of false-positive results, and it has been recommended that this assay should be used in laboratories only as an addition or substitute for direct immunofluorescence tests (Waner, J. L. et al, J. Clin. Microbiol., 1991 29 479).
As well as the problems mentioned above with the currently available rapid assays for influenza, there are other fundamental deficiencies in some of these methods. Firstly, none of the available assays can detect influenza B, which means that even a negative test result would leave the physician uncertain about the type of therapy that should be used. Secondly, if a rapid immunoassay method depends on the use of antibodies to one of the influenza A proteins, there may be a serious problem in detecting new strains of the virus which have undergone a drift or shift in the structure of the antigenic proteins. Influenza A is notorious for its propensity to undergo such changes.
Another type of rapid assay for influenza viruses has been described in a series of patent specifications (see for example Liav, A. et al, PCT Patent Application No. 92/12256). The method involves the use of a chromogenic substrate for the influenza neuraminidase enzyme. In other words the assay depends on visualising a dye, which is formed when the influenza neuraminidase cleaves a special sialic acid-dye conjugate molecule. This technique appears to offer limited specificity, because it could not readily distinguish between the presence of viral neuraminidase and other forms of the enzyme, particularly bacterial neuraminidase. It may also have low sensitivity because of the relatively slow activity of viral neuraminidase.
Influenza A and B have two major surface glycoproteins, hemagglutinin (HA) and the enzyme neuraminidase (NA), which are both essential for infectivity. It is believed that HA is necessary for the virus to attach to cells whereas NA is needed for release of the virus from cell surfaces. There are typically about 600 trimeric HA and about 50 copies of the NA tetramer units on the surface of each virus particle. Both HA and NA therefore are attractive potential targets in the search for anti-influenza drugs, but to date no anti-influenza drugs that work at either of these sites are available for clinical use.
Influenza virus hemagglutinin binds to the sialic acid containing glycoproteins and glycolipids on cell-surface receptors, thereby initiating the process of attachment of the virus to a cell and subsequent infection. The strength of the binding of a virus particle to the cell membrane appears to depend on the interaction of multiple copies of the influenza HA with multiple sialic acid groups on the cell surface.
Using this concept of a polyvalent interaction, several workers have reported the synthesis of macromolecules containing two or more sialic acid derivatives which act as hemagglutinin inhibitors. Although some strong HA inhibitors have been discovered, none of these polyvalent macromolecules has been shown to prevent influenza infection in vivo. Recent papers by Whitesides and co-workers (J. Amer. Chem. Soc., 1996 118 3789-3800; J. Medicinal Chem., 1995 38 4179-4190) have summarised the various efforts which have used this approach to the design of inhibitors of influenza hemagglutinin.
There are several known inhibitors of NA, most of which are close analogues of neuraminic acid, the enzyme's natural substrate, such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) (Meindl et al, Virology, 1974 58 457-63). International Patent Application No. WO 91/16320 describes analogs of DANA which are very active, both in vitro and in vivo, against influenza A and B neuraminidase. One of these compounds (Compound I, designated GG167 or 4-guanidino-Neu5Ac2en) is in clinical trial, and shows promise for the treatment of influenza (Hayden, F. G. et al, J. Amer. Med. Assoc., 1996 275 295).
More recently, aromatic compounds with neuraminidase-inhibitory activity have been described in U.S. Pat. No. 5,453,533 by Luo et al and U.S. Pat. No. 5,512,596 by Gilead Sciences, Inc., and analogues of compound (I), in particular compounds in which the side-chain at carbon 6 is ether-linked, have been described in International Patent Application No. WO 96/26933 by Gilead Sciences, Inc. and in C. Kim et al, J. Amer. Chem. Soc., 1997 119 681.
Several research groups have attempted to find simpler or more potent analogues of compound (I), but reports to date (e.g. Bamford M. J., J. Chem. Soc. Perkin Trans. I, 1995, 1181) indicate that any changes to

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