TOMINAGA FUKAZAWA - Academia.edu (original) (raw)
Papers by TOMINAGA FUKAZAWA
Journal of Pharmacological and Toxicological Methods, May 1, 2010
Non-specific adsorption (NSA) of drugs to plastic or glass containers used in clinical use is wel... more Non-specific adsorption (NSA) of drugs to plastic or glass containers used in clinical use is well known, but methods for reducing NSA have been rarely reported. We assessed the NSA to various containers and then investigated methods to reduce NSA. Probe drugs (methotrexate, warfarin, chloroquine, propranolol, verapamil, digoxin and paclitaxel) dissolved in water were incubated in conventional or low-adsorption containers for 4h at 4 degrees C and the NSA was determined by HPLC. They were also dissolved in aqueous methanol or acetonitrile and the NSA to a conventional polypropylene microplate was determined. Finally, tissue culture microplates were coated with silane coupling agents and the effects of the coatings were evaluated. Hydrophobic drugs (paclitaxel, verapamil and digoxin) were highly adsorbed to conventional plastic microplates, but in addition to hydrophobic drugs, positively charged drugs were well adsorbed to the tissue culture microplate. Low-adsorption microplates could reduce NSA below 15%, but positively charged or neutral hydrophobic drugs showed relatively higher adsorption. Acetonitrile showed stronger NSA inhibition than that of methanol, but the peak shapes of methotrexate and chloroquine were broadened and split. Among the silane coupling agents, GPTMS suppressed the NSA below 10%. Also, AATMS resembled the NSA pattern of GPTMS, but it increased the adsorption of methotrexate to 29%. On conventional plastic microplates, NSA is mainly driven by hydrophobic interactions, but on tissue culture microplates and low-adsorption microplates, in addition to hydrophobic interactions, ionic interactions play a role in the NSA. Therefore, to reduce the NSA to plastic containers, both hydrophobic and ionic interactions should be reduced using amphiphilic organic solvents or neutral and hydrophilic coatings.
Journal of Pharmacological and Toxicological Methods, 2009
The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-da... more The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-day system using a 24-well plate and a 10 to 21-day system using a 96-well plate have been established. Here, we modified the assay system to provide a ready-to-use Caco-2 cell monolayer using a 96-well plate in just 4 days. In our system, collagen-coated inserts and the prolongation of the culture period after seeding leads to greater Caco-2 cell proliferation and sufficient contact-inhibition. The differentiation of Caco-2 cells was enhanced, when the contact-inhibited Caco-2 cells were exposed to the differentiation-inducing agent butyric acid. The permeability to nine well-known compounds showed a statistical correlation between our 4-day system using a 96-well plate and the conventional 21-day system using a 24-well plate. We conclude that our system is more useful for evaluating many compounds for lead optimization in drug discovery.
Journal of Pharmacological and Toxicological Methods, 2009
The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-da... more The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-day system using a 24-well plate and a 10 to 21-day system using a 96-well plate have been established. Here, we modified the assay system to provide a ready-to-use Caco-2 cell monolayer using a 96-well plate in just 4 days. In our system, collagen-coated inserts and the prolongation of the culture period after seeding leads to greater Caco-2 cell proliferation and sufficient contact-inhibition. The differentiation of Caco-2 cells was enhanced, when the contact-inhibited Caco-2 cells were exposed to the differentiation-inducing agent butyric acid. The permeability to nine well-known compounds showed a statistical correlation between our 4-day system using a 96-well plate and the conventional 21-day system using a 24-well plate. We conclude that our system is more useful for evaluating many compounds for lead optimization in drug discovery.
Kluwer Academic Publishers eBooks, Mar 24, 2006
Archives of Virology, Mar 1, 1990
Kluwer Academic Publishers eBooks, Dec 2, 2005
Antimicrobial Agents and Chemotherapy, May 1, 1997
The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) pro... more The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) protease is a crucial step in the formation of infectious HIV-1 virions. In this study, we examine whether particles produced in the presence of inhibitors of HIV-1 protease can subsequently undergo gag polyprotein cleavage with restoration of infectivity following removal of the inhibitors. Viral particles produced during 7 days of culture in the presence of the protease inhibitors KNI-272 (10 M) and saquinavir (5 M) contained predominantly p55 gag polyprotein but little or no p24 gag cleavage product. Following resuspension of the particles in medium free of the inhibitor, some gag polyprotein processing was detected in particles produced from the KNI-272-treated cells, but not from the saquinavir-treated cells within the first 3 h. However, the majority of the protein remained as p55 gag throughout a 48-h experimental period. The infectivity (50% tissue culture infective dose per milliliter) of the viral particles from KNI-272-treated cells was 10 6-fold lower than that of control particles and did not significantly increase over the 48 h after the inhibitor was removed, despite the apparent return of protease function in a subset of these virions. This failure to restore infectivity was due neither to a reduction in the number of particles produced by protease inhibitor-treated cells nor to a failure of HIV RNA to be packaged in the virions. These particles also failed to express the mature phenotype by electron microscopy. Thus, while some processing of the gag polyprotein can occur in isolated HIV virions, this does not appear to be sufficient to restore infectivity in the majority of particles. This finding suggests that there may be constraints on postbudding polyprotein processing in the production of viable particles. These results should have positive implications regarding the use of protease inhibitors as anti-HIV drugs.
Bioorganic & Medicinal Chemistry, Feb 1, 2003
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activati... more We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
Jikken Dobutsu, 1991
The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rat... more The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rats was examined. Intracerebrally (ic) inoculated newborns developed severe pantropic infections resulting in emaciation, stunted growth, diarrhea, dehydration and icterus, and died 13 to 15 days after the inoculation. Newborns inoculated intraperitoneally (ip) developed similar, but milder diseases. The virus replicated in all the organs tested, which was followed by severe viremia. Histopathologically, diffuse vacuolation and necrosis of the hepatocytes were observed in the liver. Juvenile rats inoculated with the virus showed neither clinical signs nor histopathologic lesions, although viral recovery and antibody production were observed. Thus, we conclude that the UT-1 strain of RV caused asymptomatic infections in juvenile rats, and fatal infections with hepatic lesions in newborn rats. KEY WORDS : jovenile rat, newborn rat, pathogenesis, rat virus Rat virus (RV), a member of the family Parvoviridae, is one of the common viruses in laboratory rat colonies and often causes asymptomatic infections in adult rats, and severe diseases in fetal and newborn rats [1, 7, 11,14-16]. Little attention, however, has been paid to the RV infection in laboratory rat colonies in Japan, since there has been no information about it. We have isolated new RV strains in Japan from asymptomatic adult rats and have found the Japanese isolates to have hemagglutination patterns differing from those of the RV-13 prototype strain [5].
Cette invention concerne une composition medicale qui permet d'administrer un medicament ayan... more Cette invention concerne une composition medicale qui permet d'administrer un medicament ayant une activite inhibitrice de protease de VIH, et qui permet d'obtenir un effet curatif plus important. Cette composition, qui consiste en un medicament contre le SIDA, comprend du KNI-272 et au moins un compose qui est utilise comme ingredient actif principal et qui possede une activite inhibitrice de protease de VIH (virus d'immunodeficience humaine). Ce compose est choisi dans le groupe des composes generalement designes sous les noms de sakinavir, ritonavir, indinavir et nelfinavir. Le KNI-272 et l'ingredient actif sont presents dans des quantites et selon des proportions qui permettent d'obtenir un effet curatif synergique.
Antimicrobial Agents and Chemotherapy, 1997
The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) pro... more The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) protease is a crucial step in the formation of infectious HIV-1 virions. In this study, we examine whether particles produced in the presence of inhibitors of HIV-1 protease can subsequently undergo gag polyprotein cleavage with restoration of infectivity following removal of the inhibitors. Viral particles produced during 7 days of culture in the presence of the protease inhibitors KNI-272 (10 microM) and saquinavir (5 microM) contained predominantly p55gag polyprotein but little or no p24gag cleavage product. Following resuspension of the particles in medium free of the inhibitor, some gag polyprotein processing was detected in particles produced from the KNI-272-treated cells, but not from the saquinavir-treated cells within the first 3 h. However, the majority of the protein remained as p55gag throughout a 48-h experimental period. The infectivity (50% tissue culture infective dose per ...
Experimental Animals, 1991
The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rat... more The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rats was examined. Intracerebrally (ic) inoculated newborns developed severe pantropic infections resulting in emaciation, stunted growth, diarrhea, dehydration and icterus, and died 13 to 15 days after the inoculation. Newborns inoculated intraperitoneally (ip) developed similar, but milder diseases. The virus replicated in all the organs tested, which was followed by severe viremia. Histopathologically, diffuse vacuolation and necrosis of the hepatocytes were observed in the liver. Juvenile rats inoculated with the virus showed neither clinical signs nor histopathologic lesions, although viral recovery and antibody production were observed. Thus, we conclude that the UT-1 strain of RV caused asymptomatic infections in juvenile rats, and fatal infections with hepatic lesions in newborn rats. KEY WORDS : jovenile rat, newborn rat, pathogenesis, rat virus Rat virus (RV), a member of the family Parvoviridae, is one of the common viruses in laboratory rat colonies and often causes asymptomatic infections in adult rats, and severe diseases in fetal and newborn rats [1, 7, 11,14-16]. Little attention, however, has been paid to the RV infection in laboratory rat colonies in Japan, since there has been no information about it. We have isolated new RV strains in Japan from asymptomatic adult rats and have found the Japanese isolates to have hemagglutination patterns differing from those of the RV-13 prototype strain [5].
Chemical and Pharmaceutical Bulletin, 2000
Bioorganic & Medicinal Chemistry, 2003
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activati... more We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
Archives of Virology, 1990
Journal of Medicinal Chemistry, 1999
We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) prot... more We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural charateristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1′ site, and 2-methylbenzylcarboxamide group as the P2′ ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.
Archiv der Pharmazie, 1998
Journal of Pharmacological and Toxicological Methods, May 1, 2010
Non-specific adsorption (NSA) of drugs to plastic or glass containers used in clinical use is wel... more Non-specific adsorption (NSA) of drugs to plastic or glass containers used in clinical use is well known, but methods for reducing NSA have been rarely reported. We assessed the NSA to various containers and then investigated methods to reduce NSA. Probe drugs (methotrexate, warfarin, chloroquine, propranolol, verapamil, digoxin and paclitaxel) dissolved in water were incubated in conventional or low-adsorption containers for 4h at 4 degrees C and the NSA was determined by HPLC. They were also dissolved in aqueous methanol or acetonitrile and the NSA to a conventional polypropylene microplate was determined. Finally, tissue culture microplates were coated with silane coupling agents and the effects of the coatings were evaluated. Hydrophobic drugs (paclitaxel, verapamil and digoxin) were highly adsorbed to conventional plastic microplates, but in addition to hydrophobic drugs, positively charged drugs were well adsorbed to the tissue culture microplate. Low-adsorption microplates could reduce NSA below 15%, but positively charged or neutral hydrophobic drugs showed relatively higher adsorption. Acetonitrile showed stronger NSA inhibition than that of methanol, but the peak shapes of methotrexate and chloroquine were broadened and split. Among the silane coupling agents, GPTMS suppressed the NSA below 10%. Also, AATMS resembled the NSA pattern of GPTMS, but it increased the adsorption of methotrexate to 29%. On conventional plastic microplates, NSA is mainly driven by hydrophobic interactions, but on tissue culture microplates and low-adsorption microplates, in addition to hydrophobic interactions, ionic interactions play a role in the NSA. Therefore, to reduce the NSA to plastic containers, both hydrophobic and ionic interactions should be reduced using amphiphilic organic solvents or neutral and hydrophilic coatings.
Journal of Pharmacological and Toxicological Methods, 2009
The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-da... more The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-day system using a 24-well plate and a 10 to 21-day system using a 96-well plate have been established. Here, we modified the assay system to provide a ready-to-use Caco-2 cell monolayer using a 96-well plate in just 4 days. In our system, collagen-coated inserts and the prolongation of the culture period after seeding leads to greater Caco-2 cell proliferation and sufficient contact-inhibition. The differentiation of Caco-2 cells was enhanced, when the contact-inhibited Caco-2 cells were exposed to the differentiation-inducing agent butyric acid. The permeability to nine well-known compounds showed a statistical correlation between our 4-day system using a 96-well plate and the conventional 21-day system using a 24-well plate. We conclude that our system is more useful for evaluating many compounds for lead optimization in drug discovery.
Journal of Pharmacological and Toxicological Methods, 2009
The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-da... more The Caco-2 permeability assay is widely used for lead optimization in drug discovery. A 3 to 5-day system using a 24-well plate and a 10 to 21-day system using a 96-well plate have been established. Here, we modified the assay system to provide a ready-to-use Caco-2 cell monolayer using a 96-well plate in just 4 days. In our system, collagen-coated inserts and the prolongation of the culture period after seeding leads to greater Caco-2 cell proliferation and sufficient contact-inhibition. The differentiation of Caco-2 cells was enhanced, when the contact-inhibited Caco-2 cells were exposed to the differentiation-inducing agent butyric acid. The permeability to nine well-known compounds showed a statistical correlation between our 4-day system using a 96-well plate and the conventional 21-day system using a 24-well plate. We conclude that our system is more useful for evaluating many compounds for lead optimization in drug discovery.
Kluwer Academic Publishers eBooks, Mar 24, 2006
Archives of Virology, Mar 1, 1990
Kluwer Academic Publishers eBooks, Dec 2, 2005
Antimicrobial Agents and Chemotherapy, May 1, 1997
The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) pro... more The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) protease is a crucial step in the formation of infectious HIV-1 virions. In this study, we examine whether particles produced in the presence of inhibitors of HIV-1 protease can subsequently undergo gag polyprotein cleavage with restoration of infectivity following removal of the inhibitors. Viral particles produced during 7 days of culture in the presence of the protease inhibitors KNI-272 (10 M) and saquinavir (5 M) contained predominantly p55 gag polyprotein but little or no p24 gag cleavage product. Following resuspension of the particles in medium free of the inhibitor, some gag polyprotein processing was detected in particles produced from the KNI-272-treated cells, but not from the saquinavir-treated cells within the first 3 h. However, the majority of the protein remained as p55 gag throughout a 48-h experimental period. The infectivity (50% tissue culture infective dose per milliliter) of the viral particles from KNI-272-treated cells was 10 6-fold lower than that of control particles and did not significantly increase over the 48 h after the inhibitor was removed, despite the apparent return of protease function in a subset of these virions. This failure to restore infectivity was due neither to a reduction in the number of particles produced by protease inhibitor-treated cells nor to a failure of HIV RNA to be packaged in the virions. These particles also failed to express the mature phenotype by electron microscopy. Thus, while some processing of the gag polyprotein can occur in isolated HIV virions, this does not appear to be sufficient to restore infectivity in the majority of particles. This finding suggests that there may be constraints on postbudding polyprotein processing in the production of viable particles. These results should have positive implications regarding the use of protease inhibitors as anti-HIV drugs.
Bioorganic & Medicinal Chemistry, Feb 1, 2003
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activati... more We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
Jikken Dobutsu, 1991
The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rat... more The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rats was examined. Intracerebrally (ic) inoculated newborns developed severe pantropic infections resulting in emaciation, stunted growth, diarrhea, dehydration and icterus, and died 13 to 15 days after the inoculation. Newborns inoculated intraperitoneally (ip) developed similar, but milder diseases. The virus replicated in all the organs tested, which was followed by severe viremia. Histopathologically, diffuse vacuolation and necrosis of the hepatocytes were observed in the liver. Juvenile rats inoculated with the virus showed neither clinical signs nor histopathologic lesions, although viral recovery and antibody production were observed. Thus, we conclude that the UT-1 strain of RV caused asymptomatic infections in juvenile rats, and fatal infections with hepatic lesions in newborn rats. KEY WORDS : jovenile rat, newborn rat, pathogenesis, rat virus Rat virus (RV), a member of the family Parvoviridae, is one of the common viruses in laboratory rat colonies and often causes asymptomatic infections in adult rats, and severe diseases in fetal and newborn rats [1, 7, 11,14-16]. Little attention, however, has been paid to the RV infection in laboratory rat colonies in Japan, since there has been no information about it. We have isolated new RV strains in Japan from asymptomatic adult rats and have found the Japanese isolates to have hemagglutination patterns differing from those of the RV-13 prototype strain [5].
Cette invention concerne une composition medicale qui permet d'administrer un medicament ayan... more Cette invention concerne une composition medicale qui permet d'administrer un medicament ayant une activite inhibitrice de protease de VIH, et qui permet d'obtenir un effet curatif plus important. Cette composition, qui consiste en un medicament contre le SIDA, comprend du KNI-272 et au moins un compose qui est utilise comme ingredient actif principal et qui possede une activite inhibitrice de protease de VIH (virus d'immunodeficience humaine). Ce compose est choisi dans le groupe des composes generalement designes sous les noms de sakinavir, ritonavir, indinavir et nelfinavir. Le KNI-272 et l'ingredient actif sont presents dans des quantites et selon des proportions qui permettent d'obtenir un effet curatif synergique.
Antimicrobial Agents and Chemotherapy, 1997
The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) pro... more The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) protease is a crucial step in the formation of infectious HIV-1 virions. In this study, we examine whether particles produced in the presence of inhibitors of HIV-1 protease can subsequently undergo gag polyprotein cleavage with restoration of infectivity following removal of the inhibitors. Viral particles produced during 7 days of culture in the presence of the protease inhibitors KNI-272 (10 microM) and saquinavir (5 microM) contained predominantly p55gag polyprotein but little or no p24gag cleavage product. Following resuspension of the particles in medium free of the inhibitor, some gag polyprotein processing was detected in particles produced from the KNI-272-treated cells, but not from the saquinavir-treated cells within the first 3 h. However, the majority of the protein remained as p55gag throughout a 48-h experimental period. The infectivity (50% tissue culture infective dose per ...
Experimental Animals, 1991
The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rat... more The pathogenesis of the UT-1 strain, a newly isolated rat virus (RV), in juvenile and newborn rats was examined. Intracerebrally (ic) inoculated newborns developed severe pantropic infections resulting in emaciation, stunted growth, diarrhea, dehydration and icterus, and died 13 to 15 days after the inoculation. Newborns inoculated intraperitoneally (ip) developed similar, but milder diseases. The virus replicated in all the organs tested, which was followed by severe viremia. Histopathologically, diffuse vacuolation and necrosis of the hepatocytes were observed in the liver. Juvenile rats inoculated with the virus showed neither clinical signs nor histopathologic lesions, although viral recovery and antibody production were observed. Thus, we conclude that the UT-1 strain of RV caused asymptomatic infections in juvenile rats, and fatal infections with hepatic lesions in newborn rats. KEY WORDS : jovenile rat, newborn rat, pathogenesis, rat virus Rat virus (RV), a member of the family Parvoviridae, is one of the common viruses in laboratory rat colonies and often causes asymptomatic infections in adult rats, and severe diseases in fetal and newborn rats [1, 7, 11,14-16]. Little attention, however, has been paid to the RV infection in laboratory rat colonies in Japan, since there has been no information about it. We have isolated new RV strains in Japan from asymptomatic adult rats and have found the Japanese isolates to have hemagglutination patterns differing from those of the RV-13 prototype strain [5].
Chemical and Pharmaceutical Bulletin, 2000
Bioorganic & Medicinal Chemistry, 2003
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activati... more We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
Archives of Virology, 1990
Journal of Medicinal Chemistry, 1999
We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) prot... more We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural charateristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1′ site, and 2-methylbenzylcarboxamide group as the P2′ ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.
Archiv der Pharmazie, 1998