BL-20803, a New, Low-Molecular-Weight Interferon Inducer

2-Amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166) induced high levels of circulating interferon in mice when administered either parenterally or orally. Peak titers of interferon were found in the serum between 6 and 12 h after inoculation of the drug. Lower but significant levels of interferon were found in rat serum after administration of U-25, 166 by either the intraperitoneal or oral route, and good levels of circulating interferon were observed in cats after oral treatment. Repeated intraperitoneal doses (50 mg/kg) of U-25, 166 protected mice against intranasal encephalomyocarditis virus challenge. The minimal effective acute oral dose for antiviral activity was approximately 250 mg/kg. This was also the minimal dose that produced detectable levels of interferon. Maximum tolerated doses in mice were four to six times the minimal effective doses. A single oral treatment was protective in mice against challenge virus inoculated 24 h later. The compound protected mice from challenge with high levels of encephalomyocarditis virus, up to 20,000 mean lethal doses. Antiviral activity in mice was retained when certain minor substitutions were made in the U-25,166 structure.

mentioning

confidence: 99%

Stimulation of Murine Interferon by a Substituted Pyrimidine

Nichol

Weed

Underwood

1976

“…BL-3849A, the structure ofwhich is shown in Fig. 1, is a 7-methyl derivative of BL-20803 (14). The purpose ofthis paper is to describe the interferon-inducing capacity of this compound and its antiviral activity in a number of experimental viral infections in mice.…”

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confidence: 99%

“…In recent years there has been considerable interest in the development of nontoxic, lowmolecular-weight compounds that induce the production of interferon in vivo. A number of natural or synthetic compounds of this type, including 9-methylstreptimidone (12), CP-20,961 (3), 10-carboxymethyl-9-acridanone (7), quinacrine (2), MA-56 (15), tilorone hydrochloride (8,17), 2-amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166) (10), and BL-20803 (14), have been reported to induce interferon and have antiviral activity in a variety of experimental viral infections. Of particular interest are the compounds quinacrine, MA-56, tilorone, U-25,166, and BL-20803, which induce high levels of interferon after oral administration.…”

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confidence: 99%

Antiviral Activity of BL-3849A, a Low-Molecular-Weight Oral Interferon Inducer

Kern

Hamilton²,

Overall³

et al. 1976

Oral administration of BL-3849A to adult mice resulted in peak serum interferon titers of 4,000 units from 15 to 30 h after administration, with detectable levels persisting until 48 h. After intraperitoneal (i.p.) inoculation, peak serum interferon titers of 1,000 to 3,000 units were noted between 9 and 18 h. Multiple injections of the inducer by either route resulted in a marked decrease in the interferon response with each successive dose. In mice infected intranasally with the Rochester mouse virus strain of encephalomyocarditis virus, oral treatment with BL-3849A reduced mortality when initiated either 18 h before or 1 h after infection. In contrast, administration of drug by the i.p. route decreased mortality only if begun before infection. In mice inoculated i.p. with encephalomyocarditis virus, treatment by both the oral and the i.p. route decreased the mortality whether initiated 18 h before or 1 h after infection. Treatment by the oral, but not the i.p., route reduced mortality of mice inoculated i.p. with Semliki forest virus or Herpesvirus hominis type 2. BL-3849A appeared to be as effective as tilorone hydrochloride, but less effective than polyriboinosinic-polyribocytidylic acid, in the treatment of these viral infections of mice.

“…Several high-molecular-weight substances other than viruses can also cause cellular production of interferon and consequently protect animals against a variety of viral infections (6, 16). In addition, several relatively low-molecular-weight compounds also stimulate production of interferon in vivo (1,4,5,(9)(10)(11)(12)(13). In an effort to broaden our understanding of molecular structural requirements necessary for in vivo or in vitro interferon stimulation, we initiated a search for molecules that possess the ability to induce interferon in mice and consequently protect them from lethal virus infection.…”

mentioning

confidence: 99%

Antiviral and Interferon-Inducing Properties of 1,5-Diamino Anthraquinones

Stringfellow

Weed

Underwood

1979

A series of anthraquinones with amino substituents at the 1,5 positions were found to induce interferon in mice. A prototype compound, 1,5-bis [(3-morpholi- Interferon, a broad-spectrum antiviral protein produced by virus-infected cells, appears to be an important component of the host's antiviral defense system. Several high-molecular-weight substances other than viruses can also cause cellular production of interferon and consequently protect animals against a variety of viral infections (6, 16). In addition, several relatively low-molecular-weight compounds also stimulate production of interferon in vivo (1,4,5,(9)(10)(11)(12)(13). In an effort to broaden our understanding of molecular structural requirements necessary for in vivo or in vitro interferon stimulation, we initiated a search for molecules that possess the ability to induce interferon in mice and consequently protect them from lethal virus infection. During these studies several compounds were found to be active inducers. One of the most interesting of these agents was 1,5-bis[(3-morpholinopropyl)amino]-anthraquinone (Ia). This report summarizes our findings with Ia and three closely related structural analogs (Fig. 1).Studies were initiated to determine the kinetics of the serum interferon response, what cells produce interferon in vivo, the minimum dose needed to protect mice against virus infection, and the maximum tolerated dose when compounds were given by any of several routes.Particular attention was given to the development of a reduced ability of animals to respond to inducers when given in consecutive daily doses. It is well documented that animals and cells progressively lose their ability to respond to daily doses of the same interferon inducer (2,3,7,8,14,15,17). Such a reduced response could limit the use of inducers as effective antiviral agents, and studies were therefore undertaken to determine if such a situation could be controlled or avoided. How quickly hyporeactivity developed in response to each inducer, how long it persisted, and whether its onset could be avoided by alternating between injection of different inducers were explored.