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PubMed1987

Synthesis and ribonucleotide reductase inhibitory activity of analogues of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY).

A series of derivatives of the ribonucleotide reductase inhibitory anti-tumour agent 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY), including all the methyl analogues, have been synthesised. IMPY itself caused 50% inhibition of L1210 tumour-derived ribonucleotide reductase at a concentration of 0.39 mM, comparable with enzyme obtained from other sources. The analogues proved to be no better than IMPY, either as inhibitors of this enzyme or of the growth of L1210 cells in vitro. No correlation was apparent between biological activity and position of substitution.

Antineoplastic Agents↗
PubMed1986

Iron and haem complexation studies of 2,3-dihydro-1H-imidazo(1,2-b)pyrazole (IMPY, NSC 51143), a tumour cell ribonucleotide reductase inhibitor.

Spectrophotometric studies have been undertaken of the interaction of various iron-based systems with the anti-tumour agent, 2,3-dihydro-1H-imidazo(1,2-b)pyrazole (IMPY, NSC (51143), a ribonucleotide reductase inhibitor. No evidence was obtained of direct complexation in aqueous media at 25 degrees C between IMPY and Fe2+ (aq) (pH 1.5-6.8) or Fe3+ (aq) (pH 1.0-3.5), nor with a mu-oxo-bridged iron dimer (Fe--O--Fe) system. There was definitive spectral evidence of complexation of IMPY with protoporphyrin IX iron (II) at pH 7.4 and 12.9 both in the absence and presence of carbon monoxide bound at the haem-iron site. Binding of IMPY to protoporphyrin IX iron (III), in contrast, was not detected. Binding between IMPY and various iron sites important in biochemistry is discussed briefly, especially in relation to the structural properties of IMPY (from X-ray data) and the Fe--O--Fe bridge system in ribonucleotide reductase and model systems. The difficulties of the use of free heterocyclic nitrogenous bases in medicinal chemistry are discussed.

Antineoplastic Agents↗
PubMed1988

[Isolation and characteristics of coumarin-specific cytochrome P-450 (P-450Cho) from liver microsomes of DBA/2N mice, induced with pyrazole].

Coumarin-specific cytochrome P-450 (P-450Coh) has been isolated from liver microsomes of DBA/2N mice induced with pyrazole. The induction effect was accompanied by a 5.8-5.9-fold increase in the P-450Coh content which made up to 14.4-17% of the total cytochrome P-450 pool in the microsomes. At the final step of P-450Coh purification, variously substituted Sepharoses (hydroxyphenyl-, cholate-, aminooctyl- and t-cytochrome-b5-) were used. The optimal scheme involved solubilization of microsomes with sodium cholate, hydrophobic chromatography on octyl-Sepharose, adsorption on calcium-tartrate gel and hydrophobic ion-exchange chromatography on aminooctyl-Sepharose. According to SDS gel electrophoresis data, the purity of P-450Coh was 95% and Mr was 50,000 Da. The amino acid composition of the protein includes 445 residues. At saturating concentrations of coumarin, more than 90% of P-450Coh are represented by the high spin form. The catalytic activity of P-450Coh was studied in reactions of xenobiotics oxidation.

Animals↗
PubMed1986

Guanidinophenyl derivatives of pyrazole: synthesis and inhibitory effect on serine proteinases, blood coagulation and platelet aggregation.

Guanidinophenyl derivatives of pyrazole have been synthesized. Their inhibitory effects on (i) bovine trypsin, bovine thrombin, porcine pancreatic kallikrein catalyzed hydrolysis of p-nitro anilide of N alpha -benzoyl-arginine and (ii) blood coagulation and platelet aggregation, were investigated. The kinetic behaviour of all compounds conformed to that of a reversible competitive inhibition pattern, and they were also found to act in vitro as inhibitors of platelet aggregation induced by ADP.

Animals↗
PubMed1985

Studies in spiro heterocycles. Part 4(1): Investigation of the reactions of fluorinated 3-aroylmethylene-indol-2-ones with hydrazine and phenylhydrazine and synthesis of spiro [indole-3,3'-pyrazol]-2-ones.

Reactions of various 3-aroylmethylene-indol-2-ones with hydrazine and phenylhydrazine under exactly similar conditions have been carried out. The reaction with phenylhydrazine has not been investigated earlier. It was found that although the reaction with hydrazine hydrate afforded a spiro derivative viz., spiro[3H-indole-3,3'-(3H)pyrazol]-2(1H)-one, that with phenylhydrazine yielded simply a hydrazone derivative. Representative spiro compounds have been screened for antifertility activity but none was found active at a dose of 10 mg/kg in adult female rats.

Animals↗
PubMed1985

Gangrene of the hand and forearm after inadvertent intra-arterial injection of pyrazole. A case report.

A case of gangrene of the hand following inadvertent intra-arterial injection of a pyrazole derivative (Tomanol) is presented. Gangrene of the hand and superficial sloughing of the distal arm necessitated a forearm amputation. Because of the serious sequelae, precautions must be taken to avoid inadvertent intra-arterial injections and due consideration must be given to the anatomical variation of the brachial artery and its branches in the cubital fossa.

Adult↗
PubMed1979

Influence of chlorpromazine, diazepam, imipramine and pyrazole on ethanol-induced changes in activity of some enzymes in isolated rat liver.

Studies on the isolated rat liver showed distinct interaction of chlorpromazine, diazepam and imipramine with ethanol. Injected intraperitoneally in doses of 20 mg/kg, these drugs distinctly influenced elimination of ethanol, although not as strongly as pyrazole in vitro in the concentration of 20 mg/100 ml. On the other hand, ethanol altered the effect of these substances on the glucose curve, lactate and pyruvate levels, and activities of glutamic pyruvic and oxalacetic transaminases and aldolase.

Animals↗
PubMedDate not supplied

Phase I clinical evaluation of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole.

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole, a DNA synthesis inhibitor, was given to 25 patients in a phase I study. The drug was administered by rapid iv infusion daily x 5 days at 3-week intervals at doses ranging from 150 to 1500 mg/m2/day. Side effects were observed with doses of greater than or equal to 1000 mg/m2/day and included nausea and vomiting, diarrhea, dark urine, and anemia. At doses of 1500 mg/m2, three patients had evidence of hemolysis (two had hemoglobinuria and one had acute intravascular hemolysis). The hemolysis was severe enough to cause death in one patient and necessitated abandoning further dose escalation. There was minimal or no myelosuppression at any dose level. No objective tumor regression was observed in any of the 16 patients evaluable for response. Further studies are recommended to carefully evaluate the etiology of the hemolysis before proceeding to a phase II trial. It is unlikely that this drug will prove to be useful unless methods for circumventing hemolysis are developed.

Adult↗
PubMed1982

Pharmacological activities of a homologous series of pyrazole derivatives including quantitative structure-activity relationships (QSAR).

In a series of fourteen 1-benzoyl-3-methyl-pyrazole derivatives the antiinflammatory activity in the carrageenin edema of the rat paw was found to be in the potency range of that of aminophenazone. This holds also true of the analgesic, anticonvulsive, and anticholinergic activity of the compounds whereas antihistaminergic activity was 10-fold better and acute toxicity was less than that of aminophenazone. Using the MASCA model as a multivariate method in QSAR the regression matrix of the derivatives substituted in p-position of the benzoyl moiety has been calculated. According to that, all of the biological activities are mainly described in terms of pi, sigma, xi, and L. The increase of inflammatory activity could be expected by substitution of electro-positive substituents of short length (L) and little relative surface tension (xi). Concomitantly, analgesic and anticonvulsive activities could increase whereas anticholinergic and antihistaminergic activities are expected to decrease. The HANSCH analysis is surely to be preferred in investigations of the relationship between physicochemical parameters of compounds and a certain biological activity evoked by them. However, the multivariate MASCA model could be of some advantage in the optimization of chemical structure against the whole profile of biological activities in a series of compounds. Some problems of the MASCA model are briefly discussed.

Analgesics↗
PubMed1981

Neurochemical studies of an analgesic, 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole [difenamizole].

For the purpose of clarifying the action mechanism of the analgesic agent, difenamizole (DFZ), chemically known as 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole, the following properties were investigated: 1) monoamine metabolizing enzymes, 2) biosynthesis of dopamine (DA), 3) binding of DA on the synaptic membrane of mice, 4) uptake of catecholamine (CA) by synaptosome in discrete brain areas and 5) DA release from the striatal slices of mice. Pertinent results obtained are delineated below: 1) DFZ at 10(-4) M inhibited the monoamine oxidase (MAO) activity to some extent although it had no activity on catechol-O-methyltransferase (COMT) at 10(-6) -10(-4) M. 2) DFZ significantly enhanced the DA accumulating activity of pargyline in the striatum. 3) DFZ inhibited the binding of 3H-DA to synaptic membrane by 25% at 10(-4) M in the striatum. 4) DFZ inhibited the DA uptake by 50% at 10(-4) M though the activity was somewhat weaker than imipramine or cocaine on the striatum. 5) DFZ inhibited the DA release due to high K+ concentration in striatal slices at 10(-4) -5x10(-4) M. From the above data, it was concluded that DFZ may exert its analgesic effect by inhibiting the release of DA and preventing the binding of DA with the receptors.

Adenosine Triphosphatases↗
PubMedDate not supplied

[Antiamnestic properties of pyrazole dicarboxylic acid derivatives in rats].

Eight derivatives of pyrazole dicarboxylic acid (IEM-565, IEM-476, IEM-1332, IEM-474, IEM-373, IEM-440, IEM-1333, IEM-439) have been studied in rats for the ability to abolish the amnesia of passive avoidance behavior induced by electroconvulsive shock IEM-476, IEM-373 and IEM-439 have proved to be the most efficacious.

Amnesia↗
PubMed1983

Potentiation of 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity by 2,3-dihydro-1H-imidazolo[1,2-b]pyrazole in the human promyelocytic leukemic cell, HL-60.

The effect of IMPY (2,3-dihydro-1H-imidazolo[1,2-b]pyrazole) on the metabolism and cytotoxicity of subsequently administered 1-beta-D-arabinofuranosylcytosine (ara-C) was examined in the human promyelocytic leukemic cell line HL-60. Cells exposed to 3 mM IMPY for 12 hr followed by a 1-hr exposure to 1 microM [3H]ara-C accumulated 27.5 +/- 4.8 (S.D.) pmol ara-C/10(6) cells compared to 14.0 +/- 3.5 pmol/10(6) cells in untreated controls. Cells experienced greater than a 2-fold increment in 1-beta-D-arabinofuranosylcytosine 5'-triphosphate generation and retention following this same IMPY exposure and nearly a 4-fold increment in incorporation of ara-C into HL-60 nucleic acids. These alterations in ara-C metabolism were associated with a 36% reduction in the intracellular concentration of deoxycytidine 5'-triphosphate and reductions in deoxyadenosine 5'-triphosphate and deoxyguanosine 5'-triphosphate concentrations to undetectable levels. Coincubation of cells with IMPY along with other pyrimidine antagonists such as thymidine, N-(phosphonacetyl-L-aspartate), deoxyadenosine, and deoxyguanosine, produced up to 4-fold increments in ara-C intracellular accumulation. Pretreatment of HL-60 cells with 3 mM IMPY followed by a continuous exposure to 10 nM ara-C produced synergistic inhibitory effects on both suspension culture growth and soft agar clonogenicity. In contrast, exposure of normal human bone marrow progenitor cells (CFU-GM) to the same schedule of IMPY and ara-C produced subadditive or antagonistic effects on the growth of these cells in soft agar. These findings may have implications for the design of in vivo regimens using IMPY and ara-C.

Antineoplastic Agents↗
PubMed1983

[Synthesis of pyrazole derivatives and pyrazolo[4,3-d]pyrimidines. I].

Three series of pyrazole derivatives (III a-g), (IV a-g) and (V a-g) were synthesized and tested for analgesic, antipyretic and antiinflammatory activity. Many of tested compounds showed interesting analgesic and antipyretic activity, whereas no compounds exhibited any antiinflammatory activity.

Animals↗
PubMed1984

[Heterocyclic compounds with potential anti-inflammatory activity containing a 4-aminophenylalkanoic acid residue. V. Derivatives of 2,4-dihydro-3H-pyrazole-3-one].

The synthesis and pharmacological study of some derivatives of 2,4-dihydro-3H-pyrazol-3-one of general formula (I) are described. The compound in which R = C6H5 and R' = CH3 [2-(4- carboxymethylphenyl )-4-phenyl-5-methyl-2,4- dihydropyrazol -3-one] (MG 18949) proved to have antipyretic activity equal to that of ibuprofen and aminopyrine.

Analgesics↗
PubMed1980

Studies on the pharmacology and cytokinetics of 2,3-dihydro-1H-imadazo[1,2-b]pyrazole (NSC 51143) with P815 mastocytoma cells.

A study has been made of the biochemical, cytokinetic, and pharmacological effects of pyrazole-imidazole (NSC 51143) (IMPY) on P815 mastocytoma ascites cells maintained in mice and of cells maintained in culture. The distribution phase of IMPY equivalents from the peritoneal fluid of the mouse was found to be two hr, with an elimination phase of 69 hr. No consistent alteration in the ribonucleotide pools of the ascites tumor cells in vivo was observed by high-pressure liquid chromatography using i.p. doses of IMPY up to 1000 mg/kg (25% increase in survival). Correspondingly, no significant alteration occurred in the proportion of cells in G0, G1, S, or G2 + M in vivo by flow cytometric analysis. This is in contrast to the in vitro data which showed a signifcant blockage in S phase (50% effective dose, 1.6 x 10(-4) M). Using Dowex 1 chromatography of extracts from ascites tumor cells treated with IMPY in vivo, several intracellular drug metabolites were detected, and their proportion was noted to change with time. No such metabolism was detected in vitro. Some radiolabeled drug was detected in RNA and DNA from the cold, acid-insoluble fraction of ascites tumor cells. Analysis of alkaline sucrose sedimentation indicated that part of the radiolabeled IMPY was in the heavy-sedimenting DNA fraction.

Animals↗
PubMed1980

Effect of 2,3-dihydro-1 H-imidazo[1,2-b]pyrazole on the proliferation of mouse leukemic and normal cells in vivo.

Administration of 2,3-dihydro-1 H-imidazo[1,2-b]pyrazole (IMPY; NSC 51143), 250 to 500 mg/kg, in Day 5 L1210 and P388 (ascites) tumor-bearing mice did not consistently prolong the life span of tumor-bearing animals. Flow cytometry and autoradiographic studies showed that, after 12 to 18 hr of a single IMPY injection, both P388 and L1210 tumor cells were synchronized in S phase. In contrast, IMPY inhibited cellular proliferation in both bone marrow and duodenal crypts during the first 24 hr. and a recovery was detectable only after 36 hr, returning to pretherapy values by 72 hr. Preliminary data indicate that this differential response of normal versus tumor cells to IMPY can be exploited to maximize chemotherapeutic efficacy in scheduled chemotherapy with cycle-specific agents.

Animals↗
PubMedDate not supplied

Clinical toxic effects of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) with relevant pharmacokinetic parameters.

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) is an inhibitor of ribonucleotide reductase and of DNA synthesis selected for clinical trials because of its activity against L1210 leukemia variants resistant to other inhibitors of this enzyme. A phase I trial designated to allow in-depth pharmacologic evaluation has recently been completed and the clinical results and preliminary pharmacokinetic data are reported here. Each patient received IMPY by three different schedules. A single iv bolus, intermittent 5-day bolus, and 5-day continuous infusion were given at 3-week intervals. The major dose-limiting toxic effects were vomiting, rbc hemolysis, confusion, and somnolence. All toxic effects seemed to be dose- and schedule-dependent and were readily reversible. IMPY enters the cerebrospinal fluid and is highly concentrated in gastric secretions. Clearance of IMPY is impaired in the presence of hepatic insufficiency. Eighteen of 26 patients entered are evaluable for response, including one patient with colon cancer with minimal response and three patients with stable disease.

Adult↗