Publications by authors named "Shozo Kobayashi"

20 Publications

  • Page 1 of 1

Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists.

Bioorg Med Chem Lett 2016 09 25;26(17):4205-10. Epub 2016 Jul 25.

Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion.
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http://dx.doi.org/10.1016/j.bmcl.2016.07.056DOI Listing
September 2016

Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.

Bioorg Med Chem 2015 Jan 21;23(1):89-104. Epub 2014 Nov 21.

Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.
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http://dx.doi.org/10.1016/j.bmc.2014.11.018DOI Listing
January 2015

Discovery of novel chiral diazepines as bombesin receptor subtype-3 (BRS-3) agonists with low brain penetration.

Bioorg Med Chem Lett 2014 Feb 2;24(3):750-5. Epub 2014 Jan 2.

Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.
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http://dx.doi.org/10.1016/j.bmcl.2013.12.106DOI Listing
February 2014

Flavonoid biosynthesis-related genes in grape skin are differentially regulated by temperature and light conditions.

Planta 2012 Oct 9;236(4):1067-80. Epub 2012 May 9.

Grape and Persimmon Research Station, National Institute of Fruit Tree Science, National Agriculture and Food Research Organization, NARO, Akitsu 301-2, Higashi Hiroshima, Hiroshima 739-2494, Japan.

Temperature and light are important environmental factors that affect flavonoid biosynthesis in grape berry skin. However, the interrelationships between temperature and light effects on flavonoid biosynthesis have not been fully elucidated at the molecular level. Here, we investigated the effects of temperature and light conditions on the biosynthesis of flavonoids (anthocyanins and flavonols) and the expression levels of related genes in an in vitro environmental experiment using detached grape berries. Sufficient anthocyanin accumulation in the grape skin was observed under a low temperature (15 °C) plus light treatment, whereas high temperature (35 °C) or dark treatment severely suppressed anthocyanin accumulation. This indicates that the accumulation of anthocyanins is dependent on both low temperature and light. qRT-PCR analysis showed that the responses of three MYB-related genes (VlMYBA1-3, VlMYBA1-2, and VlMYBA2) to temperature and light differed greatly even though the products of all three genes had the ability to regulate anthocyanin biosynthesis pathway genes. Furthermore, the expression levels of other MYB-related genes and many flavonoid biosynthesis pathway genes were regulated independently by temperature and light. We also found that temperature and light conditions affected the anthocyanin composition in the skin through the regulation of flavonoid biosynthesis pathway genes. Our results suggest that low temperature and light have a synergistic effect on the expression of genes in the flavonoid biosynthesis pathway. These findings provide new information about the relationships between environmental factors and flavonoid accumulation in grape berry skin.
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http://dx.doi.org/10.1007/s00425-012-1650-xDOI Listing
October 2012

Seasonal abscisic acid signal and a basic leucine zipper transcription factor, DkbZIP5, regulate proanthocyanidin biosynthesis in persimmon fruit.

Plant Physiol 2012 Feb 21;158(2):1089-102. Epub 2011 Dec 21.

Laboratory of Pomology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.

Proanthocyanidins (PAs) are secondary metabolites that contribute to plant protection and crop quality. Persimmon (Diospyros kaki) has a unique characteristic of accumulating large amounts of PAs, particularly in its fruit. Normal astringent-type and mutant nonastringent-type fruits show different PA accumulation patterns depending on the seasonal expression patterns of DkMyb4, which is a Myb transcription factor (TF) regulating many PA pathway genes in persimmon. In this study, attempts were made to identify the factors involved in DkMyb4 expression and the resultant PA accumulation in persimmon fruit. Treatment with abscisic acid (ABA) and an ABA biosynthesis inhibitor resulted in differential changes in the expression patterns of DkMyb4 and PA biosynthesis in astringent-type and nonastringent-type fruits depending on the development stage. To obtain an ABA-signaling TF, we isolated a full-length basic leucine zipper (bZIP) TF, DkbZIP5, which is highly expressed in persimmon fruit. We also showed that ectopic DkbZIP5 overexpression in persimmon calluses induced the up-regulation of DkMyb4 and the resultant PA biosynthesis. In addition, a detailed molecular characterization using the electrophoretic mobility shift assay and transient reporter assay indicated that DkbZIP5 recognized ABA-responsive elements in the promoter region of DkMyb4 and acted as a direct regulator of DkMyb4 in an ABA-dependent manner. These results suggest that ABA signals may be involved in PA biosynthesis in persimmon fruit via DkMyb4 activation by DkbZIP5.
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http://dx.doi.org/10.1104/pp.111.191205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271745PMC
February 2012

Structure-activity relationships of 1,3-benzoxazole-4-carbonitriles as novel antifungal agents with potent in vivo efficacy.

Chem Pharm Bull (Tokyo) 2011 ;59(3):341-52

Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

A series of 1,3-benzoxazole-4-carbonitriles was synthesized and evaluated for its antifungal activity, solubility, and metabolic stability. Among those compounds, 4-cyano-N,N,5-trimethyl-7-[(3S)-3-methyl-3-(methylamino)pyrrolidin-1-yl]-6-phenyl-1,3-benzoxazole-2-carboxamide (16b) exhibited potent in vitro activity against Candida species, higher water solubility, and improved metabolic stability compared to lead compound 1. Compound 16b showed potent in vivo efficacy against mice Candida infection models and good bioavailability in rats.
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http://dx.doi.org/10.1248/cpb.59.341DOI Listing
June 2011

Haplotype composition at the color locus is a major genetic determinant of skin color variation in Vitis × labruscana grapes.

Theor Appl Genet 2011 May 11;122(7):1427-38. Epub 2011 Feb 11.

National Institute of Fruit Tree Science, Hiroshima, Japan.

Skin color is one of the most important fruit traits in grape, and has become greatly diversified due to hybridization and human selection. Many studies concerning the genetic control of grape color in European species (Vitis vinifera L.), especially the role of MYB-related genes, have been reported. On the other hand, there have been few studies of the MYB-related genes in grapes belonging to V. ×labruscana L.H. Bailey, a subgroup of grapes that originated from the hybridization of V. labrusca with V. vinifera. In the present study, we found a novel functional haplotype, HapE2 (consisting of the genes VlMYBA2 and VlMYBA1-3), in diploid V. ×labruscana. Moreover, we developed a method to determine the haplotype compositions of tetraploid grapes by means of quantitative real-time PCR, and investigated the relationship between haplotype composition and skin color. The color locus in V. ×labruscana grapes usually consists of functional haplotypes (HapE1 and/or HapE2), and non-functional haplotype HapA. The number of functional haplotypes in the genome was found to be correlated with the level of anthocyanin in the skin. Anthocyanin contents of grapes that contained HapE2 were significantly higher than those containing HapE1. These results suggest that the number and kind of functional haplotypes at the color locus are the major genetic factors that determine skin color variation. These findings provide new knowledge about the unique genetic control of color in V. ×labruscana grapes, and should contribute to development of new cultivars that have the desired color and anthocyanin content.
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http://dx.doi.org/10.1007/s00122-011-1542-7DOI Listing
May 2011

Inhibition of ergosterol synthesis by novel antifungal compounds targeting C-14 reductase.

Med Mycol 2010 Jun;48(4):613-21

Kasai R&D Center, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan.

The limited number of clinically available antifungal drugs for life-threatening fungal infections has produced an increased demand for new agents. In the course of our screening for novel antifungals, we identified aminopiperidine derivatives which exhibit antifungal activities against the major pathogenic yeasts. Thin layer chromatography (TLC) analysis of the extracted non-saponifiable lipids from Candida albicans showed that these compounds inhibited the ergosterol production in the late step of the synthesis pathway. The results of an LC/Q-Tof MS analysis showed that abnormal sterols including predicted ignosterol, which is known to be accumulated in C. albicans ERG24 deleted mutant, were accumulated in C. albicans treated with one of these derivatives (Compound 1b). Furthermore, the partial disruption of the cell membrane of C. albicans treated with compound 1b was observed by electron microscopy analysis, suggesting its inhibition of ergosterol synthesis. Additionally, a genetic approach demonstrated that ERG24 gene would be responsible for the resistance of Saccharomyces cerevisiae against Compound 1b, strongly indicating that the enzyme targeted by Compound 1b is Erg24p. From all these data, we concluded that these aminopiperidine derivatives are novel antifungal compounds inhibiting C-14 reduction in the ergosterol synthesis pathway.
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http://dx.doi.org/10.3109/13693780903390208DOI Listing
June 2010

Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: exploration of 6-6 fused rings as alternative S1 moieties.

Bioorg Med Chem 2009 Dec 17;17(24):8221-33. Epub 2009 Oct 17.

R&D Division, Daiichi Sankyo Co, Ltd, 1-16-13, Kita-Kasai, Tokyo 134-8630, Japan.

A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure-activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.
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http://dx.doi.org/10.1016/j.bmc.2009.10.024DOI Listing
December 2009

Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: exploration of 5-6 fused rings as alternative S1 moieties.

Bioorg Med Chem 2009 Dec 31;17(24):8206-20. Epub 2009 Oct 31.

R&D Division, Daiichi Sankyo Co, Ltd, Tokyo 134-8630, Japan.

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.
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http://dx.doi.org/10.1016/j.bmc.2009.10.023DOI Listing
December 2009

DkMyb4 is a Myb transcription factor involved in proanthocyanidin biosynthesis in persimmon fruit.

Plant Physiol 2009 Dec 25;151(4):2028-45. Epub 2009 Sep 25.

Laboratory of Pomology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.

Proanthocyanidins (PAs) are secondary metabolites that contribute to the protection of the plant and also to the taste of the fruit, mainly through astringency. Persimmon (Diospyros kaki) is unique in being able to accumulate abundant PAs in the fruit flesh. Fruits of the nonastringent (NA)-type mutants lose their ability to produce PA at an early stage of fruit development, while those of the normal astringent (A) type remain rich in PA until fully ripened. The expression of many PA pathway genes was coincidentally terminated in the NA type at an early stage of fruit development. The five genes encoding the Myb transcription factor were isolated from an A-type cultivar (Kuramitsu). One of them, DkMyb4, showed an expression pattern synchronous to that of the PA pathway genes in A- and NA-type fruit flesh. The ectopic expression of DkMyb4 in kiwifruit (Actinidia deliciosa) induced PA biosynthesis but not anthocyanin biosynthesis. The suppression of DkMyb4 in persimmon calluses caused a substantial down-regulation of the PA pathway genes and PA biosynthesis. Furthermore, analysis of the DNA-binding ability of DkMyb4 showed that it directly binds to the MYBCORE cis-motif in the promoters of the some PA pathway genes. All our results indicate that DkMyb4 acts as a regulator of PA biosynthesis in persimmon and, therefore, suggest that the reduction in the DkMyb4 expression causes the NA-type-specific down-regulation of PA biosynthesis and resultant NA trait.
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http://dx.doi.org/10.1104/pp.109.146985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785967PMC
December 2009

Color recovery in berries of grape (Vitis vinifera L.) 'Benitaka', a bud sport of 'Italia', is caused by a novel allele at the VvmybA1 locus.

Plant Sci 2009 Apr 22;176(4):470-8. Epub 2009 Jan 22.

Grape and Persimmon Research Station, National Institute of Fruit Tree Science, Akitsu 301-2, Higashi-Hiroshima, Hiroshima 739-2494, Japan.

Color mutations in grape berry skin are relatively frequent events, and can be easily seen in the vineyard. Both light-red-skinned 'Ruby Okuyama' and more intense and uniform rosy-skinned 'Benitaka' (Vitis vinifera L.) are bud sports of white-skinned 'Italia'. Previously, we reported that 'Ruby Okuyama' was caused by the recovery of VvmybA1 expression, which may have occurred as a result of intra-LTR (long terminal repeat) recombination within a retrotransposon, Gret1. However, the molecular basis of the color recovery in 'Benitaka' has not been elucidated so far. Here, we found that the VvmybA1 locus of 'Benitaka' is heterozygous for the VvmybA1a allele (non-functional) and a novel VvmybA1(BEN) allele, and that VvmybA1(BEN) restored VvmybA1 transcripts. We hypothesized that VvmybA1(BEN) allele was caused by homologous recombination between VvmybA1a and VvmybA3. In addition, the content and composition of anthocyanins in berry skins differed greatly between 'Ruby Okuyama' and 'Benitaka'. The levels of expression of the genes for flavonoid 3',5'-hydroxylase (F3'5'H), O-methyltransferase (OMT), and glutathione-S-transferase (GST) were associated with differences in the anthocyanin content and composition between the two cultivars.
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http://dx.doi.org/10.1016/j.plantsci.2008.12.015DOI Listing
April 2009

Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors.

Bioorg Med Chem Lett 2008 Aug 15;18(16):4587-92. Epub 2008 Jul 15.

Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.031DOI Listing
August 2008

Genomic and genetic analysis of Myb-related genes that regulate anthocyanin biosynthesis in grape berry skin.

Theor Appl Genet 2008 Oct 24;117(6):1009-19. Epub 2008 Jul 24.

Grape and Persimmon Research Station, National Institute of Fruit Tree Science, Akitsu 301-2, Higashi-Hiroshima, Hiroshima 739-2494, Japan.

As a result of natural hybridization and human selection over millennia, the skin colors of grapes have become greatly diversified. The color is determined by the quantity and composition of anthocyanins. Color-skinned cultivars accumulate anthocyanins in their skins, whereas white-skinned cultivars do not. Myb-related transcription-factor genes such as VvmybA1 regulate anthocyanin biosynthesis. VvMYBA2r, VlmybA1-1, VlmybA1-2, and VlmybA2, which are homologs of VvmybA1, also regulate anthocyanin biosynthesis. In this study, we isolated a novel Myb-related sequence, VlmybA1-3, from cultivars of Vitis labruscana (Vitis vinifera x Vitis labrusca) by means of inverse PCR, and confirmed by means of transient gene expression assay that the gene regulates anthocyanin biosynthesis in grape berry skin. Seedlings of V. labruscana with two functional haplotypes at a region of berry color loci accumulated more anthocyanins than seedlings with a single functional haplotype. In addition, we investigated the haplotypes at the region in 35 cultivars (both V. vinifera and V. labruscana), and found certain typical characteristics. These findings will contribute to the selection of seedlings with high anthocyanin quantities in breeding programs for wine and table grapes, and will help elucidate the origin and evolution of Vitis species.
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http://dx.doi.org/10.1007/s00122-008-0840-1DOI Listing
October 2008

Expression of three expansin genes during development and maturation of Kyoho grape berries.

J Plant Physiol 2007 Dec 18;164(12):1675-82. Epub 2006 Dec 18.

Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.

Expansins are cell-wall-localized proteins that induce loosening of isolated plant cell walls in vitro in a pH-dependent manner, but exhibit no detectable hydrolase or transglycosylase activity. Three putative expansin cDNAs, Vlexp1, Vlexp2, and Vlexp3 were isolated from a cDNA library made from mature berries of the Kyoho grape. Expression profiles of the 3 genes were analyzed throughout berry development. Accumulation of the Vlexp3 transcript was closely correlated with berry softening, and expression of this gene was detected before véraison and markedly increased at véraison (onset of berry softening). Expression of Vlexp3 was berry-specific. Vlexp1 and Vlexp2 mRNA accumulation began during the expansion stage of berry development and expression increased for both genes during ripening. Vlexp1 and Vlexp2 mRNA was detected in leaf, tendril and flower tissues and Vlexp2 mRNA was additionally detected in root and seed tissues. These findings suggest that the three expansin genes are associated with cell division or expansion and berry ripening. Vlexp3, in particular, is most likely to play a role in grape berry softening at véraison.
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http://dx.doi.org/10.1016/j.jplph.2006.07.017DOI Listing
December 2007

A skin color mutation of grapevine, from black-skinned Pinot Noir to white-skinned Pinot Blanc, is caused by deletion of the functional VvmybA1 allele.

Biosci Biotechnol Biochem 2006 Jun;70(6):1506-8

Grape and Persimmon Research Station, National Institute of Fruit Tree Science, Hiroshima.

A white-wine grape, Pinot Blanc, is thought to be a white-skinned mutant of a red-wine grape, Pinot Noir. Pinot Noir was heterozygous for VvmybA1. One allele was the non-functional VvmybA1a, and the other was the functional VvmybA1c. In Pinot Blanc, however, only VvmybA1a was observed, and the amount of VvmybA1 DNA in Pinot Blanc was half that in Pinot Noir. These findings suggest that deletion of VvmybA1c from Pinot Noir resulted in Pinot Blanc.
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http://dx.doi.org/10.1271/bbb.50647DOI Listing
June 2006

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-substituted analogues at the C-2 position.

Bioorg Med Chem 2006 Mar 15;14(6):1993-2004. Epub 2005 Nov 15.

Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd, 16-13, Kita-Kasai 1-Chome, Tokyo 134-8630, Japan.

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with carbon-linked substituents, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Palladium-catalyzed cross-coupling methods were applied for the incorporation of aliphatic and aromatic substituents.
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http://dx.doi.org/10.1016/j.bmc.2005.10.043DOI Listing
March 2006

Design, synthesis, and biological activity of novel factor Xa inhibitors: improving metabolic stability by S1 and S4 ligand modification.

Bioorg Med Chem 2006 Mar 2;14(5):1309-30. Epub 2005 Nov 2.

Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, Edogawa-ku, Japan.

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.
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http://dx.doi.org/10.1016/j.bmc.2005.09.056DOI Listing
March 2006

Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites.

Bioorg Med Chem 2005 Jun;13(12):3927-54

Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.

Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.
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http://dx.doi.org/10.1016/j.bmc.2005.04.006DOI Listing
June 2005

Retrotransposon-induced mutations in grape skin color.

Science 2004 May;304(5673):982

Department of Grape and Persimmon Research, National Institute of Fruit Tree Science, Akitsu, Hiroshima 729-2494, Japan.

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http://dx.doi.org/10.1126/science.1095011DOI Listing
May 2004
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