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T Naka

Publications and source records attributed to T Naka.

At least 91 records · Page 5Linked to original sources
PubMed1994

Pharmacological profile of a novel nonpeptide angiotensin II subtype 1 receptor antagonist, TCV-116.

TCV-116, an angiotensin II (AII) receptor antagonist, is a prodrug that is converted in vivo to the active form, CV-11974. CV-11974 selectively and competitively inhibited the specific binding of [125I]AII-(Sar1,lle8) to All subtype 1 (AT1) receptors in rabbit aortic membranes (Ki = 0.64 nM) and insurmountably inhibited the AII-induced maximal contractile response of rabbit aortic strips (pD'2 = 9.97). TCV-116 inhibited the AII-induced pressor response in rats (ID50 = 0.069 mg/kg. p.o.). In spontaneously hypertensive rats (SHR), TCV-116 had a sustained antihypertensive effect (ED25 = 0.68 mg/kg, p.o.). Repeated oral administration of TCV-116 (1 mg/kg) to SHR once daily for 2 weeks reduced blood pressure by 30-50 mmHg over 24 h. The antihypertensive effects of TCV-116 correlated well with the inhibition of AII-induced contractile responses of aortic strips prepared ex vivo after administration of TCV-116. TCV-116 had sustained effects in both 2 kidney, 1 clip hypertensive rats and in 1 kidney, 1 clip hypertensive rats, but had no effect in DOCA/salt hypertensive rats. Unlike enalapril, TCV-116 had no potentiating effect on the incidence of cough induced by citric acid in guinea pigs. These results suggest that TCV-116 is a promising antihypertensive agent with once daily administration.

Angiotensin Receptor Antagonists↗
PubMed1994

Antihypertensive effects of a highly potent and long-acting angiotensin II subtype-1 receptor antagonist, (+-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), in various hypertensive rats.

The antihypertensive effects of (+-)-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H- tetrazol-5- yl)biphenyl-4-yl]methyl]-1-H-benzimidazole-7-carboxylate (TCV-116), an angiotensin II (AII) subtype-1 receptor antagonist, were studied in various hypertensive and normotensive rats, using 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl-4- yl)methyl]-imidazole, potassium salt (losartan) as a reference compound. TCV-116 is a prodrug, which is converted in vivo to the active component, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974). In spontaneously hypertensive rats (SHR) p.o. TCV-116 (0.1 mg/kg) demonstrated a sustained antihypertensive effect that lasted for more than 10 hr and the dose that reduced the blood pressure by an average of 25 mm Hg for 24 hr (ED25), was 0.68 mg/kg. Intravenous CV-11974 reduced the blood pressure with an ED25 of 0.0027 mg/kg. Repeated p.o. administration of TCV-116 (1 mg/kg) to SHR once daily for 2 weeks reduced the blood pressure by 30 to 50 mm Hg over 24 hr without any heart rate changes. The antihypertensive effects of TCV-116 correlated well with the inhibition of angiotensin II-induced contractile responses of aortic strips prepared ex vivo after p.o. administration of TCV-116. Oral TCV-116 had a sustained antihypertensive effect with ED25 of 0.03 and 0.23 mg/kg in two-kidney, one-clip and one-kidney, one-clip hypertensive rats, respectively, and was much more potent in SHR and renal-hypertensive rats than losartan.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1993

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of potential prodrugs of benzimidazole-7-carboxylic acids.

In order to improve the oral bioavailability (BA) of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimid azole - 7-carboxylic acid (3: CV-11194) and 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (4: CV-11974), novel angiotensin II (AII) receptor antagonists, chemical modification to yield prodrugs has been examined. After selective tritylation of the tetrazole rings in 3 and 4, treatment of N-tritylated benzimidazole-7-carboxylic acids (6, 7) with a variety of alkyl halides, followed by deprotection with hydrochloric acid, afforded esters of 3 and 4. Mainly 1-(acyloxy)alkyl esters and 1-[(alkoxycarbonyl)oxy]alkyl esters, double ester derivatives, were synthesized. Their inhibitory effect on AII-induced pressor response in rats and oral BA were investigated. (Pivaloyloxy)methyl and (+/-)-1-[[(cyclohexyloxy)-carbonyl]oxy]ethyl esters of 3 and 4 showed marked increases in oral bioavailability which significantly potentiated the inhibitory effect of the parent compounds on AII-induced pressor response. Among them, (+/-)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2- ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimida zole- 7-carboxylate (10s, TCV-116) was selected as a candidate for clinical evaluation.

Administration, Oral↗
PubMed1993

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids.

A series of 2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7- carboxylic acids was prepared from the key intermediate 3-amino-2-[[(biphenyl-4- yl)methyl]amino]benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-ben zimidazole- 7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats. Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10(-6)-10(-7) M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753. The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipophilicity, and electronic effects affected the potency of the AII antagonistic action. Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect. The representative compound, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 1.1 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0 x 10(-10) M). Oral administration of CV-11974 to conscious normotensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response. CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.

Angiotensin Receptor Antagonists↗
PubMed1993

Inhibition of rabbit aortic angiotensin II (AII) receptor by CV-11974, a new nonpeptide AII antagonist.

The angiotensin II (AII) antagonistic action of CV-11974 (2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylic acid) was investigated in an AII-receptor binding assay using rabbit aortic membranes and an AII-induced contraction assay using rabbit aortic strips. A single class of [125I]AII-(Sar1,Ile8) binding sites was found in the membranes with a dissociation constant (Kd) of 0.15 nM and a receptor concentration (Bmax) of 86.9 fmol/mg protein. CV-11974 markedly reduced Kd without affecting Bmax. The specific binding of [125I]AII-(Sar1,Ile8) in this preparation was inhibited completely by CV-11974 [the inhibition constant (Ki) = 0.64 nM], DuP 753 [an angiotensin II type I (AT1) receptor-selective antagonist] (Ki = 51 nM) and EXP3174 (an active metabolite of DuP 753) (Ki = 6.8 nM), but was not affected by PD123177 (an AT2 receptor-selective antagonist). These results suggest that the single binding site in rabbit aortic membranes is an AT1 receptor subtype. The affinity of CV-11974 to these AT1 receptors was approximately 80 and 10 times higher than that of DuP 753 and EXP3174, respectively. CV-11974 showed no appreciable affinity for the AT2 receptors found in bovine cerebellum. In the in vitro functional study, CV-11974 markedly reduced the AII-induced maximal contractile response of rabbit aortic strips (pD'2 = 9.97). In contrast, Compound 7-H, which lacks the carboxyl group at the benzimidazole ring of CV-11974, inhibited the contraction in a competitive manner. The inhibition by CV-11974 was long lasting. These results suggest that CV-11974 is a potent and long-acting AT1 receptor-selective, competitive antagonist. The carboxyl group at the benzimidazole ring plays an important role in the interaction between CV-11974 and the AT1 receptor.

Angiotensin II↗
PubMed1993

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles.

A series of substituted 2-butylbenzimidazoles bearing a biphenylylmethyl moiety at the 1-position was prepared via three synthetic routes and evaluated for angiotensin II (AII) receptor antagonistic activity (in vitro and in vivo). Binding affinity was determined using bovine adrenal cortical membrane. Substitution at the 4-, 5-, or 6-position reduced the affinity relative to that of the unsubstituted compound (13a). However, most of the compounds with a substituent at the 7-position showed binding affinity comparable to that of DuP 753 (losartan). In functional studies, a carboxyl group was found to be very important for antagonistic activity against AII. Comparison of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-benzimidazole-4-, -5-, -6-, and -7-carboxylic acids (15a-d) in an AII-induced rabbit aortic ring contraction assay clearly demonstrated the importance of the substitutional position of the carboxyl group. In an in vivo assay, oral administration of benzimidazole-7-carboxylic acids caused long-lasting inhibition of the AII-induced pressor response in rats. The optimum substituent at the 7-position of the benzimidazole ring was found to be a carboxyl or an ester group. The representative compound, 2-butyl-1-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxy lic acid (15d, CV-11194), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 5.5 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11194 (IC50 value, 5.5 x 10(-11) M), while the compound had no effect on the contraction induced by norepinephrine or KCl. Orally administered CV-11194 at doses of 0.3-10 mg/kg dose-dependently inhibited the AII-induced pressor response in rats and dogs. CV-11194 at 1 mg/kg po reduced blood pressure in spontaneously hypertensive rats (SHR). The three-dimensional molecular structure of CV-11194 was determined by X-ray diffraction.

Adrenal Cortex↗
PubMed1993

[Angiotensin II receptor antagonist activities and mode of action of benzimidazole-7-carboxylic acid derivatives].

Blockade of the action of angiotensin II (A II) is a target for development of novel antihypertensive agents. We have recently discovered a novel and potent nonpeptide AT1 selective A II receptor antagonists, benzimidazole-7-carboxylic acid derivatives (CV-11194 and CV-11974), which are more potent than DuP 753. The prodrug analogue (TCV-116) of CV-11974 is an orally active, highly potent and long-acting antihypertensive agent. The structure-activity relationships (SAR) of benzimidazole derivatives showed the importance of presence of a 7-carboxyl group for the potent and functionally non-competitive (insurmountable) A II antagonism. The interactions between the A II antagonist and receptor on the basis of SAR studies as well as A II receptor modeling are also described.

Angiotensin Receptor Antagonists↗
PubMed1993

Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV-11974), and its prodrug, (+/-)-1-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5- yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116).

The angiotensin II (AII) antagonistic action of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzi mid azole-7 - carboxylic acid (CV-11974) was examined in in vitro assay systems, including AII receptor binding assay using membrane fractions of bovine adrenal cortex or rabbit aorta and AII-induced contraction assay using rabbit aortic strips, and CV-11974 and its prodrug, (+/-)1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), were examined in an in vivo system of AII-induced pressor response in conscious rats. DuP 753 or EXP3174 (the main active metabolite of DuP 753) was used as the reference compound. CV-11974 inhibited the binding of [125I] AII to the bovine adrenal cortical membrane and rabbit aortic membrane with IC50 values of 1.12 x 10(-7) and 2.86 x 10(-8) M, respectively. Similar results were obtained with EXP3174. CV-11974 interacted with AII in these membrane fractions with subtype 1 receptor in a competitive manner. CV-11974 at 10(-5) M did not affect the binding of [125I]AII to subtype 2 (AT2) receptor in bovine cerebellum. CV-11974 selectively inhibited the AII-induced contraction of rabbit aortic strips in a noncompetitive manner (pD' 2, 9.97); it had no effects on the contraction induced by norepinephrine, KCl, serotonin, prostaglandin F2 alpha or endothelin. EXP3174 showed a pD'2 value of 8.95 for the AII-induced contraction. CV-11974 given intravenously and TCV-116 given orally inhibited the AII-induced pressor response in rats with ID50 values of 0.033 mg/kg and 0.069 mg/kg, respectively. These effects of CV-11974 and TCV-116 were 12 and 48 times more potent than those of EXP3174 and DuP 753, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1991

[A case of paraneoplastic neuropathy with necrotizing arteritis localized in the peripheral nervous system].

A 59-year-old demented Japanese man who was proven to have high titer of serum alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA) was admitted to our hospital. Neurological examinations revealed moderate dementia with deterioration and loss of memory, and decreased deep tendon reflexes in all extremities. Sensory disturbances were not obvious. There were no significant changes in the usual laboratory findings including CSF, except for elevated serum AFP and CEA. Three months after admission, he died of gastric cancer and its metastases in liver and lymph nodes. Post-mortem examination in the central nervous system (CNS) revealed many senile plaques and neurofibrillary tangles throughout the cerebral cortex and hippocampus. There was marked loss of neurons in the hippocampus. All the neuropathological findings in the CNS were consistent with those in Alzheimer disease. In the peripheral nervous system, necrotizing arteritis was found throughout the length of sciatic nerve. Large myelinated fibers seemed to be preferentially degenerated with proximo-distal gradient. Teased fiber preparation revealed de/remyelination and axonal degeneration more frequently at the distal portion. Immunohistologically, the serum IgG of this patient specifically reacted to the endothelial cells of all vessels in control organs, which strongly suggested the autoimmune mechanism for the necrotizing arteritis in this patient. The pathogenetic role of this antibody for necrotizing arteritis, found selectively in the peripheral nervous system, still remained unclear. However, paraneoplastic neuropathy due to necrotizing arteritis is a distinct entity in addition to common form of paraneoplastic subacute sensory neuropathy.

Alzheimer Disease↗
PubMed1989

Ovarian involvement as an initial manifestation of malignant lymphoma.

An immunohistochemical study of a rare initial manifestation of non-Hodgkin's lymphoma (NHL) in the ovaries is presented. There have been very few reports to date on immunohistochemical studies of lymphoma involving the ovaries. A 53-year-old woman suffering from lower abdominal pain and abnormal genital bleeding was diagnosed as having a tumor in her left ovary by ultrasonic echograms and CT scanning. The patient underwent a simple total hysterectomy and bilateral salpingo-oophorectomies. The tumor, measuring 14 x 10 x 10 cm, was located in the left ovary and extended to the major omentum, mesocolon and left ureter. The histology of the tumor was that of NHL showing diffuse proliferation of small cleaved cells. Immunohistochemical studies of the ovarian tumor showed that the tumor cells were of a B-cell lymphoma nature with LCA+, MB-1+, lambda+, keratin-, IgG-, IgM-, IgA-, kappa-, and MT-1-. Although the main lesion involved the ovary, the case could not be identified definitely as primary lymphoma of the ovary.

Female↗
PubMed1988

Inhibitory effect of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H-pyrazol o[3, 4-d]pyrimidine-2-carboxylate (AA-2379) on type III allergic (Arthus) reaction.

Methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H- pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379), a non-steroidal, non-acidic agent, markedly inhibits type III allergic (Arthus) reaction; the ID50 values of AA-2379 in the rat reversed passive Arthus pleurisy, the rat active Arthus pleurisy, and the reversed passive Arthus reaction in rat skin were 5-10 mg/kg, p.o., and 30 mg/kg of AA-2379 inhibited the active Arthus reaction in rabbit skin by about 50%. Dexamethasone, but not acidic non-steroidal anti-inflammatory drugs and aminopyrine, inhibited the Arthus reaction. The vascular permeability in the reversed passive Arthus pleurisy is enhanced biphasically in the early response mediated by physiologically active amines, prostaglandins, and leukotrienes, and in the late response mediated by complements and polymorphonuclear leukocytes (PMNs). AA-2379 inhibited the late response more potently than the early one. Furthermore, when given after the early response was reduced, AA-2379 obviously inhibited the late response. Rat zymosan-induced paw edema and mouse zymosan-activated serum-induced peritonitis, mediated by complements, were dose-dependently inhibited by AA-2379; the ID50 values were 11.4 and 10.2 mg/kg, p.o., respectively. The results suggest that AA-2379 differs from non-steroidal anti-inflammatory agents in strongly inhibiting the late response of the Arthus reaction, which associated with PMNs.

Animals↗
PubMed1988

Antiinflammatory, analgesic, and antipyretic activities of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H-pyrazol o[3, 4-d]pyrimidine-2-carboxylate (AA-2379), a novel non-acidic agent.

The antiinflammatory, analgesic, and antipyretic activities of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H-pyrazolo[ 3, 4-d]pyrimidine-2-carboxylate (AA-2379), a novel non-acidic agent, were examined. 1. AA-2379 had a potent antiinflammatory activity; 3-25 mg/kg, p.o. of the compound inhibited rat carrageenin-, bradykinin-, trypsin-, formalin-, dextran-, and nystatin-induced paw edema; mouse traumatic edema; and rat croton oil pouch inflammation by about 30%. The compound at 25-50 mg/kg, p.o. also inhibited the vascular permeability induced by histamine, serotonin, and bradykinin. 2. AA-2379 had an analgesic activity; the ID50 values in mouse phenylquinone-induced writhing were 10.1 mg/kg, p.o. and the compound at 12.5 mg/kg, p.o. inhibited dog urate arthritis. 3. AA-2379 at 3-10 mg/kg, p.o. showed antipyretic activity in febrile rats and rabbits. 4. AA-2379, at 500 mg/kg, p.o. was not ulcerogenic in rats. 5. These data show that AA-2379 is more active than non-acidic antiinflammatory agents, such as tiaramide and aminopyrine.

Animals↗
PubMed1986

Validity of transfer-function representation of input-output relation in allosteric models.

A transfer-function representation of reaction velocity is devised to describe analytically and approximately an input-output response of allosteric enzyme around a steady state. The transfer function is derived on assuming an exponential change in reaction velocity for the indicial response to substrate influx rate. The validity of the representation with variation in the kinetic parameters and flow rates is examined for the response of Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) dimeric models by comparing with the exact response obtained from the computer simulation, that is, by numerical integration of the rate equation. The representation has a wider valid region with a decrease in influx rate than with an increase. For the KNF model the representation is valid for negative cooperativity, but invalid for positive cooperativity. For the MWC model the validity decreases with stronger cooperativity. With the transfer functions valid for the Michaelis-Menten and allosteric reactions, we may derive the transfer-function representation for many metabolic pathways.

Allosteric Regulation↗
PubMed1984

T4 RNA ligase mediated preparation of novel "chemically misacylated" tRNAPheS.

T4 RNA ligase was employed for the condensation of Escherichia coli tRNAPhe missing cytidine-75 and adenosine-76 (tRNAPhe-COH; the acceptor "oligomer") with each of several chemically acylated derivatives of pCpA (the donor "oligomer"). The resulting "chemically misacylated " tRNAPheS were obtained in 20-65% yields following chromatographic workup on DEAE-cellulose and benzoylated DEAE-cellulose. Characterization of the chemically misacylated tRNAs was accomplished by (i) enzymatic reaminoacylation of chemically misacylated tRNAPhe with phenylalanine by E. coli phenylalanyl-tRNA synthetase following chemical deacylation of the "incorrect" amino acid, (ii) comparison of the hydrolytic effects of Cu2+ solutions on chemically and enzymatically prepared samples of N-acetyl-L-phenylalanyl- tRNAPheS , and (iii) measurement of the chromatographic behavior of the tRNA species derived from chemical misacylation .

Escherichia coli↗
PubMed1983

Dipeptide formation with misacylated tRNAPhes.

Several misacylated P-site tRNAs have been prepared by the T4 RNA ligase-mediated coupling of Escherichia coli tRNAPhe missing the 3'-terminal cytidine and adenosine moieties and N-acetylaminoacyl-pCpA derivatives. The reaction proceeded in reasonable yield in each case and the tRNA products were purified conveniently by successive chromatographies on DEAE-cellulose and benzoylated DEAE-cellulose. The misacylated tRNAPhes were assayed for participation in the peptidyltransferase reaction, using E. coli ribosomes and poly(U) as message. When phenylalanyl-tRNAPhe was employed as the A-site tRNA, "chemically aminoacylated" N-acetyl-L-phenylalanyl-tRNAPhe produced dipeptide to virtually the same extent as authentic N-acetyl-L-phenylalanyl-tRNAPhe, which was prepared by enzymatic activation of tRNAPhe followed by chemical acetylation. Significant dipeptide formation was also obtained with N-acetyl-L-tyrosyl-tRNAPhe, but much less dipeptide was obtained when the D-isomers of these two N-acetylaminoacyl-tRNAs were employed in the same assay system. Interestingly, N-acetyl-beta-phenylalanyl-tRNAPhe formed dipeptide at least to the same extent as authentic N-acetyl-L-phenylalanyl-tRNAPhe.

Acylation↗