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PubMed1994

Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2,2,2-trifluoroethyl)-4- [[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively.

Angiotensin Receptor Antagonists↗
PubMed1999

Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives.

Novel pyrimidinyl pyrazole derivatives were synthesized and examined for cytotoxic and antitumor activity. Mannich reaction was employed to construct this scaffold. Among the compounds synthesized, a series of propene derivatives exhibited a potent cytotoxic activity against some tumor cell lines including multidrug resistant cell lines due to the overexpression of P-glycoprotein. The vinyl bond moiety in the scaffold was believed to be required for the cytotoxic activity. Among them, compound 14 g, when administered intraperitoneally, showed potent antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice. This compound also showed high activity against a solid tumor Meth A mouse fibrosarcoma when administered both intraperitoneally and orally.

Animals↗
PubMed1990

Antineoplastic effect of the combination of 2,3-dihydro-1H-pyrazole[2,3a]imidazole plus deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine in mice with L1210 leukemia cells.

Administration of 2,3-dihydro-1H-pyrazole[2,3a]imidazole (IMPY, 150 mg/kg) followed 8 hr later by injection of deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine (dAdo/EHNA, 175 mg/17.5 mg/kg) on days 2, 3, 6, and 7 increased the mean survival time of L1210 tumor bearing mice (210%). The sequential treatment was more efficacious than the simultaneous administration of these drugs. Administration of IMPY or dAdo/EHNA, alone, at the same doses as in the combination, did not prolong the life-span of tumor bearing mice. To determine the basis for the increased survival due to the sequential treatment with IMPY and dAdo/EHNA, cell cycle analysis and deoxyribonucleoside triphosphate concentrations were measured. Cytotoxicity of IMPY and dAdo/EHNA is known to be achieved through the inhibition of ribonucleotide reductase. IMPY is a specific inhibitor of the nonheme-iron subunit of ribonucleotide reductase, whereas deoxyadenosine in the presence of the adenosine deaminase inhibition, EHNA, is converted to deoxyadenosine 5'-triphosphate (dATP), which is a specific inhibitor of the effector-binding-subunit of ribonucleotide reductase. Our studies showed that L1210 cells accumulated in early S-phase, whereas intracellular dATP and deoxyguanosine triphosphate (dGTP) pools were depleted 8 hr after IMPY administration. dAdo/EHNA administration 8 hr after IMPY injection caused an increase in the intracellular concentration of dATP while maintaining the depletion of the dGTP pool and prolonged the S-phase as compared to the administration of IMPY alone.

Adenine↗
PubMed2003

A pyrazole derivative, YM-58483, potently inhibits store-operated sustained Ca2+ influx and IL-2 production in T lymphocytes.

In nonexcitable cells, Ca(2+) entry is mediated predominantly through the store depletion-dependent Ca(2+) channels called store-operated Ca(2+) (SOC) or Ca(2+) release-activated Ca(2+) channels. YM-58483, a pyrazole derivative, inhibited an anti-CD3 mAb-induced sustained Ca(2+) influx in acute T cell leukemia, Jurkat cells. But it did not affect an anti-CD3 mAb-induced transient intracellular Ca(2+) increase in Ca(2+)-free medium, nor anti-CD3 mAb-induced phosphorylation of phospholipase Cgamma1. It was suggested that YM-58483 inhibited Ca(2+) influx through SOC channels without affecting the TCR signal transduction cascade. Furthermore, YM-58483 inhibited thapsigargin-induced sustained Ca(2+) influx with an IC(50) value of 100 nM without affecting membrane potential. YM-58483 inhibited by 30-fold the Ca(2+) influx through SOC channels compared with voltage-operated Ca(2+) channels, while econazole inhibited both SOC channels and voltage-operated Ca(2+) channels with an equivalent range of IC(50) values. YM-58483 potently inhibited IL-2 production and NF-AT-driven promoter activity, but not AP-1-driven promoter activity in Jurkat cells. Moreover, this compound inhibited delayed-type hypersensitivity in mice with an ED(50) of 1.1 mg/kg. Therefore, we concluded that YM-58483 was a novel store-operated Ca(2+) entry blocker and a potent immunomodulator, and could be useful for the treatment of autoimmune diseases and chronic inflammation. Furthermore, YM-58483 would be a candidate for the study of capacitative Ca(2+) entry mechanisms through SOC/CRAC channels and for identification of putative Ca(2+) channel genes.

Anilides↗
PubMed1999

[A new class of N-methyl-D-aspartic acid receptor agonists and antagonists--derivatives of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids].

New agonists and antagonists of the N-methyl-D-aspartic acid (NMDA) receptors were found among the derivatives of 1- or 2-alkyl-substituted imidazole-4,5- and pyrazole-3,4-dicarboxylic acids. Lipophilic surrounding of the nitrogen atom in these compounds was found to determine their ability to be either agonists or antagonists, while the distance between the terminal acidic functions was the same. An increase in the lipophilicity can also cause loss of selective action upon the NMDA receptors and occurrence of non- NMDA antagonistic activity.

Animals↗
PubMedDate not supplied

Antiproliferative activity and mechanism of action of DZ-3358, a novel pyrimidinyl pyrazole derivative.

The novel pyrimidinyl pyrazole derivative, 1-[5-methyl-1-(2-pyrimidinyl) -4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinyl]-1-trans-propene hydrochloride (DZ-3358), was found through random screening to exhibit anti-proliferative activity against human and murine cancer cell lines. DZ-3358 induced the mitotic arrest of P388 murine leukemia cells at 0.4 microgram/ml in a time-dependent manner, and inhibited porcine tubulin polymerization. Furthermore, using immunofluorescence techniques, we observed microtubule formation in NUGC-3 human gastric cancer cells treated with DZ-3358. Microtubule formation was disordered, similar to that which occurred when such cells were treated with colchicine. These findings suggest that the mechanism of the anti-proliferative effect of DZ-3358 is the inhibition of mitosis due to the blocking of tubulin polymerization. The differential pattern of growth inhibitory concentrations of DZ-3358 against a series of cancer cell lines was compared with that of colchicine and vincristine, and no correlation was found with the pattern of these two drugs. DZ-3358 may be useful as a new type of tubulin inhibitor and anti-cancer drug.

Animals↗
PubMed2001

Novel pyrazole cannabinoids: insights into CB(1) receptor recognition and activation.

Synthesis of an antagonist, SR141716A, that selectively binds to brain cannabinoid (CB(1)) receptors without producing cannabimimetic activity in vivo, suggests that recognition and activation of cannabinoid receptors are separable events. In the present study, a series of SR141716A analogs were synthesized and were tested for CB(1) binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, and hypothermia in mice. These analogs retained the central pyrazole structure of SR141716A with replacement of the 1-, 3-, 4-, and/or 5-substituents by alkyl side chains or other substituents known to impart potent agonist activity in traditional tricyclic cannabinoid compounds. Although none of the analogs alone produced the profile of cannabimimetic effects seen with full agonists, several of the 3-substituent analogs with higher binding affinities showed partial agonism for one or more measures. Cannabimimetic activity was most noted when the 3-substituent of SR141716A was replaced with an alkyl amide or ketone group. None of the 3-substituted analogs produced antagonist effects when tested in combination with 3 mg/kg Delta(9)-tetrahydrocannabinol (Delta(9)-THC). In contrast, antagonism of Delta(9)-THC's effects without accompanying agonist or partial agonist effects was observed with substitutions at positions 1, 4, and 5. These results suggest that the structural properties of 1- and 5-substituents are primarily responsible for the antagonist activity of SR141716A.

Analgesics, Non-Narcotic↗
PubMed2001

Formation of unusual glutamate conjugates of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423) and its analogs: the role of gamma-glutamyltranspeptidase in the biotransformation of benzylamines.

The role of gamma-glutamyltranspeptidase (GGT) in transferring glutamate from endogenous glutathione (GSH) to the benzylamine moiety of a compound, such as 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423), is described. Studies were performed with structurally related analogs of DPC 423 to demonstrate that this type of reaction was common to compounds possessing a benzylamine group. Synthesizing appropriate standards and confirming by liquid chromatography (LC)/mass spectroscopy and LC/NMR made unambiguous assignments of the structures of glutamate conjugates of DPC 423. The use of stable isotope-labeled GSH for metabolism studies has not been described before. In the present study, we report the novel use of deuterated GSH in conjunction with mass spectral analysis to demonstrate the glutamate transfer to the benzylamines in the presence of GGT. To further demonstrate that the alpha protons on the benzylamines and glutamate (as part of glutathione) were unaffected during the transpeptidation, these protons were replaced with deuterium. Acivicin (AT-125), a potent and selective inhibitor of GGT, was used to abolish the formation of the glutamate conjugates of DPC 423 in vitro and in vivo. This provided further evidence of the role of GGT in forming the glutamate conjugates of benzylamines. This study demonstrated conclusively that GGT was responsible for mediating the transfer of glutamic acid from GSH to the benzylamine moiety of a series of structurally related compounds.

Animals↗
PubMed1975

Polysubstituted pyrazoles. Part 2: Sulphonamidophenylhydrazone-2-pyrazolin-4-ones and sulphonamidophenylazopyrazoles as potential anticancer agents.

The synthesis of some new derivatives of 1-[4-nitrophenyl]-5-[4-substituted sulphonamidophenylhydrazono]-2-pyrazolin-4-ones and 3,5-dimethyl-4-[4-substituted sulphonamidophenylazo]-pyrazoles is described. Bromination of ethyl 2-[nitrophenylhydrazono]-3-oxobutyrates in dry benzene afforded the 4-bromo derivatives which upon cyclization gave high yields of the 4-hydroxpyrazoles. Many other new intermediates were prepared and the results of the UV and IR spectral studies are discussed.

Antineoplastic Agents↗
PubMed1975

Effect of pyrazole administration on the isopropanol induced fatty liver.

The isopropanol induced fatty liver is prevented in the rat by prior administration of pyrazole. Acetone administration, on the other hand, determines an increase in the hepatic triglyceride level. These results suggest the implications of acetone in the induction of the fatty liver following acute isopropanol administration in the rat.

1-Propanol↗
PubMed2002

Microwave induced diastereoselective synthesis of spiro[indole-oxiranes] and their conversion to spiro[indole-pyrazoles].

The microwave induced diastereoselective synthesis of spiro[3H-indole-3,2'-oxiranes]-3'-benzoyl-2 (1H)-one is reported. Epoxidation of 3-aroylmethylene indole-2-one 1 with alkaline H2O2 under microwave irradiation in an open vessel under controlled conditions yields a diastereomeric pair of spiro[3H-indole-3,2'-oxiranes]-3'-benzoyl-2 (1H) ones 2 and 3 in 65-85% yield. The stereoselectivity depends upon the reaction time and power output. The spiro[indole-pyrazoles] 4 have been synthesised by the reaction of 2 with hydrazine hydrate. Under the same condition 3 gave the mixture of products. All synthesised compounds have been screened in vitro for their antifungal activity against Rhizoctonia solani, Fusarium oxysporum and Collectotrichum capsici and antitubercular activity against Mycobacterium tuberculosis.

Antifungal Agents↗
PubMed1976

Cell cycle synchronization of human lymphoid cells in vitro by 2,3-dihydro-1h-imidazo[1,2-b]pyrazole.

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY), a DNA synthesis-inhibitory drug, reversibly arrests growth of human lymphoblasts in vitro. DNA distribution histograms of cultures exposed to 0.5 to 2.0 mM IMPY show accumulation of cells with G1-early S DNA content. On reincubation in fresh medium, cell cycle traverse is resumed by the blocked cells in a synchronized manner. Maximum incorporation of [H3]thymidine into DNA (174 to 220% of control) and labeling indexes (72 to 86%) are seen after 4 hr of incubation, and a major increase in cell number is seen between the 9th and 13th hr. DNA distribution histograms of cells reincubated in fresh medium (after double block), show an initial increase in the number od cells with S-G2-M DNA content and a corresponding decrease in the number of G1-early S cells. After 4 hr of reincubation, a gradual increase in the number of G1-early S cells was seen as the earlier blocked cells completed cell cycle traverse and mitosis. Cells exposed to 2.0 mM IMPY took approximately 2 hr longer to traverse than did cells exposed to 0.5 mM IMPY.

Cell Division↗
PubMed1992

4H-thieno[3,4-c]pyrazole derivatives with antiinflammatory, analgesic, antipyretic and platelet antiaggregating activities.

The synthesis of a series of 1-aryl-1,6-dihydro-4H-thieno[3,4-c]pyrazol-4-ones by cyclization of 3-[(2-arylhydrazino)methylene]thiophene-2,4(3H,5H)-diones, prepared by reacting 3-dimethylaminomethylenethiophene-2,4(3H,5H)-dione with arylhydrazines, is described. The 4-fluorophenyl derivative showed remarkable analgesic, antiinflammatory and antipyretic activities in mice or rats, as well as a platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid.

Acetates↗
PubMed1991

Antinociceptive property of new 4-acyl-arylhydrazone pyrazole compounds.

A series of new 4-acyl-arylhydrazone pyrazole compounds were tested for antinociceptive activity using the inhibition of abdominal contortions induced by acetylcholine (4 mg/kg, ip) in the mouse. Dipyrone was used for comparison of the antinociceptive potency of the compounds being tested. All drugs were administered po in saline (dipyrone) or in propylene glycol (4-acyl-arylhydrazones). The maximum response induced by dipyrone (86% inhibition) was assigned an efficacy index of 1.0. Although none of the compounds had an efficacy index greater than 1.0, all three reached 1.0. The two most potent compounds, W1d and W1g, which also had an efficacy similar to that of dipyrone, contain a p-N(CH3)2 and m-OH,p-OCH3 group in the aromatic ring of the acyl-hydrazone, respectively. W1d presented the lowest antinociceptive ED50 in the series (1.41 mg/kg) and was eleven times more potent than dipyrone (ED50 = 15.80 mg/kg). Other substitutions at the para position had lower potency than W1d. The present results indicate that the introduction of a group at the para position of the acyl-arylhydrazone ring increases the antinociceptive activity of these compounds to provide compounds of the same efficacy but greater potency than dipyrone to which these new compounds are structurally related. Other assays of nociceptive activity are being used to characterize the mechanism of action of the potential new drugs.

Abdomen↗
PubMed1990

[Interaction of coumarin-hydroxylating cytochrome P-450coh from liver microsomes of mice induced by pyrazole with cytochrome b5].

Cytochrome P-450coh from pyrazole-treated mice was shown to form a tight and specific complex with cytochrome b5 from mouse liver microsomes. The complex formation was found to result in type I spectral changes indicating a spin shift from the low to the high spin form. When added to a reconstituted system containing cytochrome P-450coh, NADPH-cytochrome P-450 reductase and phospholipid, cytochrome b5 stimulates hydroxylation of coumarin and O-deethylation of 7-ethoxycoumarin. The maximal stimulating effect is reached at a 1:1 stoichiometry. Mouse liver cytochrome b5 stimulates hydroxylation and deethylation by 100% and 60%, respectively. The stimulating effect of cytochrome b5 was found to result from the increase of the maximal rate of oxidation, being practically without effect on Km. Cytochrome b5 purified from rat and rabbit liver microsomes interacts with cytochrome P-450coh but fails to stimulate the oxidation reaction. At large excess, cytochrome b5 inhibits the oxidations catalyzed by cytochrome P-450coh. Immobilized cytochrome b5 either from mouse or rat and rabbit microsomes proved to be an efficient affinity matrix for cytochrome P-450coh purification.

Animals↗
PubMedDate not supplied

Synthesis and CNS activity of some new substituted indeno [1,2-c] pyrazoles.

Some new 1-(6'-substituted-4'-methylquinol-2'-yl)-3-methyl-indeno[1,2- c]pyrazoles (Va-d) have been synthesized by the condensation of 2-acetylindane-1,3-dione (I) with 2-hydrazino-4-methyl-6-substituted quinolines (IIa-d), followed by cyclodehydration with polyphosphoric acid and Wolff-Kishner reduction. Compounds (IVa-d) showed noticeable CNS activity.

Animals↗