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PubMed1980

Pyrazole prevention of CC14-induced ultrastructural changes in rat liver.

Carbon tetrachloride (CC14) administration to rats leads to an early dilatation, vesiculation and disorganization of the liver endoplasmic reticulum (ER). This hepatotoxin also causes detachment of ribosomes from ER membranes, dilatation of the Golgi cisternae and occasionally dilatation of the perinuclear membrane. Prior treatment of the rats with pyrazole completely prevents CC14- induced ultrastructural alterations observed in liver at 3 h. This drug is known to decrease the intensity of the irreversible binding of CC14 reactive metabolites to cellular constituents without modifying the intensity of the CC14- induced lipid peroxidation, either in vitro or in vivo, as measured by the diene conjugation procedure or by decreases inthe arachidonic acid content of microsomal phospholipids. Results suggest that interaction of reactive metabolites rather than lipid peroxidation mediates deleterious effects of CCl4 on the liver ER.

Animals↗
PubMedDate not supplied

Preclinical toxicologic study of 2,3-dihydro-1H-imidazo[1,2-b] pyrazole (IMPY) in mice, dogs, and monkeys.

Single-treatment schedules in mice and dogs and multiple-treatment schedules in dogs and monkeys were used to evaluate the toxicity of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole. The LD50 of the iv single dose in male and female mice collectively was 993 mg/kg (2980 mg/m2). The major target organs in mice, dogs, and monkeys were the bone marrow, lymphoid tissue, and gastrointestinal tract. Clinical signs at lethal and high toxic doses were weight loss, diarrhea, hematochezia, emesis, anorexia, mydriasis, dyspnea, lethargy, and stupor. The immediate toxic effect on blood cells was a depression of rbcs with suppression of lymphoid elements occurring later. In dogs, the most toxic schedule was single bolus injections. Attenuation of toxic responses occurred if rest periods were introduced between single or repeated daily dose schedules. The monkeys were more sensitive than the dogs to the high toxic dose on a milligram per meter squared basis, with similar sensitivity to the low toxic dose in the repeated daily injections.

Animals↗
PubMedDate not supplied

Phase I clinical trial of weekly iv 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY).

In a phase I trial, 2,3-dihydro-1H-imidazo[1,2-b]pyrazole was administered iv weekly at doses ranging from 0.1 to 3.0 g/m2/wk to patients with refractory metastatic solid tumors. Although gastrointestinal toxicity was tolerable and neither granulocyte nor platelet toxicity was seen, significant dose-limiting hemolysis was encountered at doses of 1.5 g/m2/wk. While no definite tumor regressions were seen in the 32 patients evaluable for response, two patients (squamous cell carcinoma of lung and tonsil) had clinically useful improvement.

Antineoplastic Agents↗
PubMed1993

Novel adenosine receptor ligands: 1,3-disubstituted[1]benzopyrano[2,3-c]pyrazol-4-ones. Synthesis and structure-activity relationships.

A series of 1,3-disubstituted[1]benzopyrano[2,3-c]pyrazol-4-ones were synthesized and tested in vitro as A1 and A2 adenosine receptor ligands. The binding results and a molecular modelling study indicated that the presence of a proton donor group in the N6-H region of adenosine and the 7-NH region of xanthine, respectively and occupancy of the A2 lipophilic area by a moiety endowed with an electrostatic effect are essential for receptor affinity and A2-selectivity.

Animals↗
PubMed1993

3-(Arylamino)-6,7-dihydro-6-methylpyrano[4,3-c]pyrazol-4(1H or 2H)-ones with antipyretic, analgesic, antiarrhythmic, hypotensive and other activities.

The synthesis of 3-(arylamino)-6,7-dihydro-6-methylpyrano[4,3-c]pyrazol-4(1H or 2H)-ones by reaction of N-aryl-5,6-dihydro-4-hydroxy-6-methyl-2-oxo- 2H-pyrano-3-carbothioamides with hydrazine is described. Some compounds showed remarkable antipyretic, analgesic, antiarrhythmic and hypotensive activity in rats or mice, as well as weak antiinflammatory, local anesthetic and in vitro platelet antiaggregating activity.

Aconitine↗
PubMedDate not supplied

[Effect of pyrazole on the activity of acetaldehyde-producing enzymes in the liver].

Influence of pyrazole on the endogenous ethanol level and activities of acetaldehyde-producing enzymes was investigated. Drastic enhancement of the endogenous ethanol level in the blood and tissues was accompanied by an insignificant increase of phosphoethanolamine lyase activity, while activity of threonine aldolase and pyruvate dehydrogenase was unchanged.

Acetaldehyde↗
PubMed1993

A comparative study of ethanol absorption in the canine jejunum after pretreatment with cyanamide or pyrazole.

This report describes the retardation of ethanol absorption from the intestinal tract and reduction of portal blood flow by high acetaldehyde concentrations in dogs using a jejunal segment with the vascular supply intact. The cyanamide-pretreatment group (CY), in which an extremely high acetaldehyde concentration developed, in comparison with the control and pyrazole-pretreated (PY) groups, showed a gradual increase of portal blood ethanol, a 25% reduction in the amount of absorbed ethanol, and an 85% smaller absorption rate constant value (Ka). These facts indicate that the presence of a high acetaldehyde concentration in the blood results in a reduction of ethanol absorption and retardation of ethanol reaching the systemic circulation. The rapid reduction of portal blood flow and the lower ethanol level in the portal vein observed in the CY group, in comparison with the other two groups, also indicate that the reduction of ethanol permeability through the absorption site to the blood is an important retarding factor induced by acetaldehyde.

Acetaldehyde↗
PubMed1995

Synthesis and pharmacological evaluation of some novel 5-(pyrazol-3-yl)thiadiazole and oxadiazole derivatives as potential hypoglycemic agents.

Four series of 5-(pyrazol-3-yl)thiadiazole and oxadiazole derivatives (Va-c, VIa-c, VIIIa-c, IXa-c) have been synthesized from 5-arylazo-3-carbethoxy-4-methoxy-1-phenylpyrazole (Ia-c) with a view to investigate their pharmacological activity. The structure of the synthesized products was inferred from elemental and spectral data. The hypoglycemic effect, antimicrobial activity and toxicity of these potential chemotherapeutic agents were evaluated. Nineteen of these products were effective, when administered at an oral dose of 100 mg/kg body weight in inducing a marked reduction in blood glucose level.

Animals↗
PubMed1997

Synthesis, cytotoxicity, antitumor activity and sequence selective binding of two pyrazole analogs structurally related to the antitumor agents U-71,184 and adozelesin.

Two pyrazole analogs structurally related to the antitumor agents adozelesin and U-71,184 respectively were synthesized. By using a polymerase chain reaction approach, both compounds show selective binding to A + T rich sequences exactly as reference compound U-71,184. In in vitro assays, against L1210 cell lines, both derivatives showed cytotoxicity in the pM range, values comparable with the natural target compound (+)-CC-1065. The most active compound showed very high antitumor activity in mice implanted with L1210 cells (ILS% 363).

Animals↗
PubMed1998

Synthesis and analgesic properties of new 5-thioaryl pyrazole derivatives.

A new series 5-thio aryl pyrazole derivatives were proposed aiming analgesic activity. In this work, 8 new compounds of this class were synthesized using usual synthetic methodology, having as key intermediate the 3-methyl-4-nitro-5-chloropyrazole-1-phenyl derivative and subsequent reaction with several nucleophiles sulfides. Pharmacological evaluation of this series showed analgesic activity in the some extent in especially for 5-(4-bromophenyl)-thio-3-methyl-4-nitro-1-phenylpyrazole which was the most potent in this series, presenting an analgesic action comparable to that show by dipyrone.

Analgesics, Non-Narcotic↗
PubMed1997

Synthesis, cytotoxicity and antitumor activity of some new simplified pyrazole analogs of the antitumor agent CC-1065. Effect of an hydrophobic group on antitumor activity.

Three simplified pyrazole analogs (7-9) of the antitumor agents CC-1065, were synthesized. In in vitro assays, against L1210 cell lines all derivatives showed a cytotoxicity in a pM range, values close to the natural target compound (+)-CC-1065. In in vivo tests, against disseminate L1210 leukemia cells, synthesized compounds showed a good potency (O.D. 300 micrograms/Kg) but no activity. These observations further validate the effect of the hydrophilic and/or hydrophobic characteristics of the substituents present on the molecules, confirming the relevance of this phenomena on in vivo activity. In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity, probably due to a worse bioavailability of the drugs in animals.

Animals↗
PubMed1998

Toxicity of a phenyl pyrazole insecticide, fipronil, to mosquito and chironomid midge larvae in the laboratory.

Toxicity of a phenyl pyrazole insecticide, fipronil, to 4th-instar larvae of 6 species of colonized mosquitoes (Aedes aegypti, Ae. albopictus, Ae. taeniorhynchus, Anopheles quadrimaculatus, Culex nigripalpus, and Cx. quinquefasciatus) and 2 species of field-collected chironomid midges (Chironomus crassicaudatus and Glyptotendipes paripes) was evaluated in the laboratory. All mosquito species were highly susceptible with 48-h median lethal concentration (LC50) values ranging from 0.00043 ppm (Ae. taeniorhynchus and An. quadrimaculatus) to 0.023 ppm (Ae. albopictus). Chironomus crassicaudatus and G. paripes also were extremely susceptible (48-h LC50 of both species: 0.00042 ppm) to fipronil. Larval mortality checks of Ae. taeniorhynchus, Cx. nigripalpus, and G. paripes at 24 h and again at 48 h posttreatment revealed delayed activity of this compound against these species. First-instar larvae of Ae. albopictus and Cx. quinquefasciatus were significantly (P < 0.01) more susceptible to fipronil than the 4th-instar larvae of these mosquito species.

Aedes↗
PubMedDate not supplied

In vitro and in vivo antiproliferative activity of IPCAR, a new pyrazole nucleoside analog.

IPCAR is a pyrazole nucleoside analog which belongs to a class of compounds structurally related to the inosine monophosphate (IMP) dehydrogenase (IMPDH) inhibitors ribavirin, selenazofurin and tiazofurin. Unlike other anticancer drugs, IPCAR showed a potent and broad-spectrum antiproliferative activity in vitro coupled with low cytotoxicity for resting PBL and CFU-GM. IPCAR proved fully inhibitory against human nasopharyngeal carcinoma KB cells expressing the MDR phenotype, whereas IPCAR-resistant renal adenocarcinoma ACHN/R1 cells were fully susceptible to inhibition by a number of anticancer drugs, with the exception of 6TG, 6MP and 5FU towards which they showed a partial cross-resistance. In combinations studies, IPCAR proved synergistic with 6MP, 6TG, 5FU and ribavirin, and additive with ara-A, MTX, doxorubicin, taxol and tiazofurin. Antagonistic effects were never observed. Although the precise molecular target of IPCAR remains to be identified, the data presented herein suggest that, unlike ribavirin and tiazofurin, this drug inhibits a step of the de novo purine biosynthesis different from the conversion of IMP into GMP. In vivo, IPCAR showed low acute toxicity (DL10 > 1000 mg/kg) and was active against the L1210 murine lymphocytic leukemia model. Drug doses of 125 and 250 mg/kg on a day-1, -3 and -5 dosing schedule increased the life span (ILS) relative to untreated control mice of 36.4 and 68.2%, respectively, whereas administration of 500 mg/kg on days 1 and 3 resulted in a ILS of 86.4% and also increased the 30-day survival rate (25% of the mice).

Animals↗
PubMed2005

Synthesis of novel N1-substituted bicyclic pyrazole amino acids and evaluation of their interaction with glutamate receptors.

N1-substituted bicyclic pyrazole amino acids (S)-9a-9c and (R)-9a-9c, which are conformationally constrained analogues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested for activity at ionotropic and metabotropic glutamate receptors. Some of them turned out to be selective for the NMDA receptors, where they behaved as weak antagonists. The biological activity is mainly due to the interaction with the glutamate binding site, and not with the glycine co-agonist site.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2006

Deep blue mixed-valent PtIIIPtIIIPtII complex [Pt3Br2(mu-pz)6] (pz=pyrazolate) showing valence-detrapping behavior in solution.

The oxidation of the pyrazolate bridged cyclic PtII trimer, [Pt3(mu-pz)6] (1), in the presence of bromide ion gave a deep blue mixed-valent Pt(II,III,III) complex, [Pt3Br2(mu-pz)6] (2). The structural analysis of 2 disclosed that the complex has localized Pt--Pt bond. Our theoretical calculations revealed that the HOMO and LUMO of Pt3 (II,III,III) species mainly consists of (dsigma-dsigma) and (dsigma-dsigma)* orbitals, respectively, and the origin of deep blue color of the bromo complex, 2, arises from the (dsigma-dsigma)-->(dsigma-dsigma)* transition. Unique fluxional behavior was observed due to valence-detrapping of 2 in solution. The activation parameters of the valence-detrapping of 2 obtained by Eyring analyses were DeltaH(not equal)=37(2) kJ mol(-1) and DeltaS(not equal)=-67(7) J mol(-1) K(-1).

Journal Article↗
PubMed2005

The tautomerism of 1H-pyrazole-3(5)-(N-tert-butyl)carboxamide in the solid state and in solution.

The X-ray crystal structure of 1H-pyrazole-3-(N-tert-butyl)-carboxamide was determined. In the solid state, the 13C and 15N CP/MAS NMR spectra correspond to this tautomer. In solution, both tautomers are present in a ratio that depends on the temperature (at 293 K, 90% 3-substituted/10% 5-substituted). Some unusual 1H, 1H couplings involving the NH proton were observed. DFT (GIAO) calculations were carried out.

Journal Article↗