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Biomedical subjects

N Ohtake

Publications and source records attributed to N Ohtake.

At least 19 recordsLinked to original sources
PubMed2001

Design, synthesis, and discovery of a novel CCR1 antagonist.

The CC chemokines may play an important role in the pathogenesis of chronic inflammatory diseases including rheumatoid arthritis, and their effects are thought to be mediated through CCR1 receptors. Several nonpeptide CCR1 receptor antagonists that showed high affinity for human CCR1 receptors have been identified; however, their effectiveness in animal models of inflammatory diseases has been scarcely demonstrated, probably due to species selectivity of the antagonists. To elucidate the pathophysiological role of CCR1 receptors in murine models of disease, we looked for a potent antagonist for both murine and human CCR1 receptors. Screening of our chemical collection for inhibition of (125)I-MIP-1alpha binding to human CCR1 receptors transfected in CHO cells led to the identification of xanthene-9-carboxamide 1a as the lead compound. Derivatization of 1a by quaternarizing the piperidine nitrogen with various alkyl groups and by installing substituents into the xanthene moiety dramatically improved the inhibitory activity against both human and murine CCR1 receptors. As a result, 2q-1 showing IC(50) values of 0.9 and 5.8 nM for human and murine CCR1 receptors, respectively, was discovered. This compound is the first murine CCR1 receptor antagonist and may be a useful tool for clarifying the role of CCR1 receptors in murine models of disease.

Amides↗
PubMed2001

Identification of a potent and nonpeptidyl ccr3 antagonist.

CCR3 is expressed in a variety of leukocyte subsets, especially eosinophils, and may be involved in allergic disorders such as atopic asthma. To clarify the pathophysiological roles of CCR3 in allergic disorders, we developed a nonpeptidyl CCR3 antagonist. This antagonist, which is referred to as "Compound X," that inhibited the binding of [(125)I]Eotaxin to CHO cells transfected with human CCR3 with an IC(50) value of 2.3 nM. In human eosinophils, Compound X also inhibited Eotaxin-induced increases in intracellular Ca(2+) concentrations and chemotaxis. Thus, Compound X appears to be a highly potent CCR3 antagonist. These findings suggest that Compound X may be a useful tool for elucidating the pathophysiological roles of CCR3 in a variety of allergic disorders.

Animals↗
PubMed2001

Rapid N transport to pods and seeds in N-deficient soybean plants.

Non-nodulated soybean (Glycine max (L.) Merr.) plants were cultivated hydroponically under N-sufficient (5 mM NaNO(3)) or N-deficient (0.5 mM NaNO(3)) conditions. (13)N- or (15)N- labelled nitrate was fed to the cut end of the stems, and the accumulation of nitrate-derived N in the pods, nodes and stems was compared. Real-time images of (13)N distribution in stems, petioles and pods were obtained using a Positron Emitting Tracer Imaging System for a period of 40 min. The results indicated that the radioactivity in the pods of N-deficient plants was about 10 times higher than that of N-sufficient plants, although radioactivity in the stems and nodes of N-deficient versus N-sufficient plants was not different. A similar result was obtained by supplying (15)NO(3) to cut soybean shoots for 1 h. The fact that the N translocation into the pods from NO(3) fed to the stem base was much faster in N-deficient plants may be due to the strong sink activity of the pods in N-deficient plants. Alternatively, the redistribution of N from the leaves to the pods via the phloem may be accelerated in N-deficient plants. The temporal accumulation of (13)NO(3) in nodes was suggested in both N-sufficient and N-deficient plants. In one (13)NO(3) pulse-chase experiment, radioactivity in the stem declined rapidly after transferring the shoot from the (13)NO(3) solution to non-labelled NO(3); in contrast, the radioactivity in the node declined minimally during the same time period.

Amino Acids↗
PubMed2001

Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity.

We evaluated the pharmacological profiles of (2R)-N-[1-(6- aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide(compound A), which is a novel muscarinic receptor antagonist with M(2)-sparing antagonistic activity. Compound A inhibited [(3)H]NMS binding to cloned human muscarinic m1, m2, m3, m4, and m5 receptors expressed in Chinese hamster ovary cells with K(i) values (nM) of 1.5, 540, 2.8, 15, and 7.7, respectively. In isolated rat tissues, compound A inhibited carbachol-induced responses with 540-fold selectivity for trachea (K(B) = 1.2 nM) over atria (K(B) = 650 nM). In in vivo rat assays, compound A inhibited acetylcholine-induced bronchoconstriction and bradycardia with intravenous ED(50) values of 0.022 mg/kg and >/=10 mg/kg, respectively. Furthermore, in dogs, compound A (0.1-1 mg/kg p.o.) dose dependently shifted the methacholine concentration-respiratory resistance curves. In mice, compound A (10 mg/kg i.v.) did not inhibit oxotremorine-induced tremor. The brain/plasma ratio (K(p)) of compound A (3 mg/kg i.v.) was 0.13 in rats; this K(p) was less than that of scopolamine (1.7) and darifenacin (0.24). The inhibition of compound A (3 mg/kg i.v.) on ex vivo binding in rat cerebral cortex was almost similar to that of NMS. These findings demonstrate that compound A has high selectivity for M(3) receptors over M(2) receptors, displays a potent, oral M(3) antagonistic activity without inhibition of central muscarinic receptors because of low brain penetration. It is well known that central muscarinic antagonists may have diverse CNS effects, and M(2) receptors regulate cardiac pacing and act as autoreceptors in the lung and bladder. Thus, compound A may have fewer cardiac or CNS side effects than nonselective compounds.

Animals↗
PubMed2000

A potent, long-acting, orally active (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: novel muscarinic M(3) receptor antagonist with high selectivity for M(3) over M(2) receptors.

A novel series of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M(3) receptor selective antagonist 1, to develop a potent, long-acting, orally active M(3) antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M(3) over M(2) receptors in comparison with the corresponding cyclopentylphenylacetic acid group. However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1-(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M(3) receptors (K(i) = 2.8 nM) over M(2) receptors (K(i) = 530 nM) in a human binding assay and good in vitro metabolic stability in dog and human hepatic microsomes was identified. This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced bronchoconstriction in dogs, and may be useful in clinical situations in which M(3) over M(2) selectivity is desirable.

Acetamides↗
PubMed2000

Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds.

Through further derivatization of J-111,347 (1a), a trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenem, undesired epileptogenicity in a rat intracerebroventricular assay (200 microg/rat) could be eliminated to afford J-111,225 (2a), J-114,870 (3a) and J-114,871 (3b) which preserved comparable broad antimicrobial activity.

Carbapenems↗
PubMed2000

Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 1: J-111,347 and related compounds.

1Beta-methylcarbapenems having various 3,5-disubstituted pyrrolidinylthio-side chains at C-2 were designed and synthesized. Evaluation of their antibacterial activities indicated that J-111,347 (1a) is the first example of an extremely broad spectrum antibiotic showing activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as Pseudomonas aeruginosa.

Anti-Bacterial Agents↗
PubMed2000

Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice.

BACKGROUND & AIMS: We showed previously that a Kampo (Chinese/Japanese herbal) medicine, Inchin-ko-to (ICKT), inhibits hepatocyte apoptosis induced by transforming growth factor beta1 in vitro. The present study investigated whether ICKT or its ingredients inhibit Fas-mediated liver apoptosis in vivo. METHODS: Acute liver injury was induced by an intravenous injection of anti-Fas antibody, Jo2. The effects of ICKT and its ingredients on lethality, histology, apoptotic index, serum transaminase levels, caspase activation, mitochondrial membrane potential (Deltapsi(m)), and mitochondrial permeability transition (MPT) were analyzed. Apoptosis in mouse hepatocytes in vitro was also evaluated. RESULTS: Pretreatment with ICKT rescued 75% of Jo2-treated mice and markedly suppressed liver apoptosis/injury. Genipin, an intestinal bacterial metabolite of geniposide that is a major ingredient of ICKT, was found to be an active principle of ICKT. Genipin also suppressed in vitro Fas-mediated apoptosis in primary-cultured murine hepatocytes. Activation of caspase 3 and 8 in the liver homogenate and rapid reduction of triangle uppsi(m) of hepatocytes isolated from Jo2-treated mice were inhibited by genipin preadministration. The resistance to Ca(2+)-induced MPT was enhanced in liver mitochondria of genipin-treated mice. CONCLUSIONS: These results suggest that the antiapoptotic activity of genipin via the interference with MPT is a possible mechanism for therapeutic effects of ICKT.

Alanine Transaminase↗
PubMed2000

Modulation of lung local immune responses by oral administration of a herbal medicine Sho-saiko-to.

Sho-saiko-to (SST), a Chinese/Japanese herbal medicine (Kampo medicine) widely used to treat chronic hepatitis in Japan, is known to modulate immune responses, and thus its immunomodulating activity may be responsible for its bi-directional effects on the lungs as therapeutic efficacy in various lung diseases and involvement in development of interstitial pneumonia. We administered SST to BALB/c mice orally and examined the lung tissue levels of pro/anti-inflammatory cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and the effects of SST on acute lung injury induced by instillation of lipopolysaccharide (LPS) or IL-1. Although SST had no effect on lung TNF-alpha or IL-1beta level, it increased IL-6. Investigation of active fractions of SST suggested that multiple ingredients were supposed to be responsible for IL-6-inducing activity. Liquiritigenin, a metabolite of liquiritin which is one of the major ingredients in SST enhanced in vitro IL-6 production in anti-CD3 monoclonal antibody (anti-CD3 mAb)-stimulated lung mononuclear cells in a cell-type specific and dose-dependent manner. SST suppressed LPS-induced lung injury at the later phase when lung leak was evident while being ineffective on initial neutrophil sequestration to the lung in these models. These findings suggest that SST modulates lung inflammation by regulating local immune response.

Administration, Oral↗
PubMed2000

Discovery of a muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors among 2-[(1S,3S)-3-sulfonylaminocyclopentyl]phenylacetamide derivatives.

In the course of developing a metabolically stable M3 receptor antagonist from the prototype antagonist, J-104129 (1), introduction of certain substituents into the cyclopentane ring of 1 was found to be effective not only in improving metabolic stability but also in greatly enhancing the subtype selectivity. Among the cyclopentane analogues, sulfonamide derivatives (10f) and (10g) displayed 160- and 310-fold selectivity for M3 over M2 receptors, and both were significantly more selective than the prototype antagonist (120-fold). Subsequent derivatization of the sulfonamide series led to the highly selective M3 receptor antagonists (10h, 10i and 10j) with >490-fold selectivity for M3 over M2 receptors. Among them, p-nitrophenylsulfonamide (J-107320, 10h) exhibited 1100-fold selectivity for M3 receptors (Ki = 2.5 nM) over M2 receptors (Ki = 2800 nM) in the human muscarinic receptor binding assay using [3H]-NMS as a radio ligand.

Alkenes↗
PubMed2000

Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems.

Novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems were designed and synthesized to provide J-111,347 (1a) as the first example of an exceptionally broad-spectrum antibiotic, showing activity against methicillin-resistant Staphyloccocus aureus (MRSA) as well as Pseudomonas aeruginosa. Further derivation of 1a afforded J-111,225 (2a), J-114,870 (3a), and J-114,871 (3b). which showed improved safety profiles and retained broad-spectrum antibacterial activities.

Animals↗
PubMed2000

Trends and characteristics in prostate cancer mortality in Japan.

BACKGROUND: In North America, the incidence and mortality of prostate cancer has been declining since the early 1990s. We calculated the age-adjusted death rates, age-specific death rates and standardized mortality ratio (SMR) for prostate cancer in Japan and analyzed their features. METHODS: Yearly age-adjusted death rates for prostate cancer were calculated by dividing the number of events by the population at risk, with direct standardization to the world population. Age-specific death rates were calculated for the 1970s, 1980s and 1990s and which age group showed the highest rate of increase was examined. The SMR in each prefecture was also calculated for each period. RESULTS: The respective number of deaths and the age-adjusted death rate was 1107 and 2.29 in 1973 and 6251 and 5.15 in 1997. The age-specific death rates showed an exponential increase with age in all three periods and the rate of increase was higher in older age groups. The distribution of SMR showed the same tendency in all three periods. The prefectures with significantly high or low SMR were distributed in clusters. CONCLUSIONS: The prostate cancer death rate is increasing rapidly in Japan. However, the age-adjusted death rate has remained stable from 1996 to 1997. How this figure will change and whether the prostate cancer death rate in Japan will begin to decline, like in North America, is of interest. The prefectures with significantly high or low SMR showed a characteristic clustered distribution pattern.

Age Distribution↗
PubMed2000

Marked reduction of mortality in salt-loaded Dahl salt-sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859.

OBJECTIVE: To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-1 05859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to confirm the potential of this compound as an ETA antagonist METHODS: Vehicle and J-105859 were administered to salt-loaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-1 05859. RESULTS: The Ki values of J-1 05859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-induced contractions in pulmonary artery (pA2 = 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-1 05859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-1 05859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-1 05859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day. CONCLUSION: J-105859 is a selective, potent, orally active ETA-selective antagonist ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

Alkanes↗
PubMed2000

[Hereditary prostate cancer].

Familial prostate cancer patients are sometimes encountered. Hereditary prostate cancer is a more specific form of familial prostate cancer that is inherited by a susceptibility gene consistent with Mendelian inheritance. Early age at onset is the most important characteristic. No clear differences in either stage, grade or prognosis have been found between hereditary and sporadic prostate cancer. No susceptibility genes have been isolated yet, but several genes may exist. In Japan, doctors are not generally aware of hereditary and familial prostate cancer. Family history is one of the most important risk factors of prostate cancer. We should make an effort to find prostate cancer patients at an early stage in the high risk families.

Adult↗
PubMed1999

J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors.

A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M3 receptors over M2 receptors. Subsequent synthetic derivatizations resulted in highly potent M3 receptor antagonists with selectivity greater than two orders of magnitude for M3 over M2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hyd roxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for M3 receptors (Ki = 4.2 nM) over M2 receptors (Ki = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K(B) value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease.

Alkenes↗