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Results for “Pyrazoles”

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PubMed1984

Metabolism of methylazoxymethanol acetate in the F344 rat and strain-2 guinea pig and its inhibition by pyrazole and disulfiram.

The basic parameters of the metabolism of methylazoxymethanol-(N,N'-methyl-14C) acetate, in terms of exhaled 14CO2, urinary metabolites, and inhibition by pyrazole and disulfiram, were examined in F344 rats and strain-2 guinea pigs. After a 18.7 mg/kg SC dose, 45% (6 h) and 49.5% (24 h) was exhaled as 14CO2, and 6.6% (24 h) of the radioactivity was excreted in the urine by the rats. After identical treatment, 36.5% (6 h) and 39.5% (24 h) was exhaled as 14CO2 and 3.5% (24 h) was excreted in the urine by the guinea pigs. Urea-14C and methylazoxymethanol(-14C) were the major urinary metabolites. In both species, pretreatment with pyrazole (40 or 360 mg/kg, IP) caused a significant reduction of exhaled 14CO2 and an increase in the amount of urinary methylazoxymethanol(-14C). Similar but less pronounced effects were observed after pretreatment of rats with disulfiram (1 g/kg, PO). These results are discussed with respect to possible enzyme systems involved in the metabolic activation of methylazoxymethanol in vivo.

Alcohol Dehydrogenase↗

PubMed1998

Induction of CYP2A5 by pyrazole and its derivatives in mouse primary hepatocytes.

Mouse liver CYP2A5 is induced by several structurally unrelated compounds. In intact mouse liver, pyrazole (PYR) and 4-hydroxypyrazole (4-OH) induce selectively the expression of CYP2A5 while expression of other CYPs is decreased. In this study we exposed mouse primary hepatocytes to PYR, 4-OH, 4-methylpyrazole (4Me; 0.1-20 mM) and 4-iodopyrazole (4-I; 0.1-5.0 mM). PYR and its derivatives increased coumarin 7-hydroxylase activity, with 4-1 and 4-OH being the strongest inducers, by 114-fold and 41-fold, respectively. However, only 4-1 treatment increased markedly the CYP2A5 protein content. CYP2B9/10-mediated pentoxyresorufin O-deethylase activity (PROD) was decreased by 80% by 4-Me and 4-1, and by 50% by 4-OH while PYR had no marked effect. PYR and 4-Me increased 2- to 3-fold the CYPA1/2-mediated ethoxyresorufin O-deethylase activity (EROD) while 4-OH and 4-1 had no marked effect on this enzyme. The time of exposure markedly affected the inducibility of 4-OH such that induction was 7-fold stronger when it was added to the incubation medium 24 h after the isolation of hepatocytes compared to exposure 3 h after their isolation. Cimetidine prevented the induction of coumarin 7-hydroxylase activity by PYR and 4-OH by 46 and 74%, respectively indicating that their effects on the expression of CYP2A5 are, at least partly, mediated via their metabolites. The data demonstrate that the regulation of CYP2A5 is different from other monooxygenases and that the effects of pyrazole and its derivatives are different in vivo and in vitro. Also, the timing of exposure markedly affects the inducibility of 4-OH in hepatocytes.

Animals↗

PubMed1989

Pyrazole treatment of rats potentiates CCL4-but not CHCL3-hepatotoxicity.

Rats were treated with pyrazole to increase the liver content of the "alcohol-inducible" form of cytochrome P-450. This treatment increased the sensitivity of these animals to CCl4-hepatotoxicity assessed by increases in SGPT and SGOT levels and decreases in microsomal cytochrome P-450 and aniline p-hydroxylase activity. However, the hepatotoxicity of CHCl3 was not increased by pyrazole-treatment. These data are consistent with the hypothesis that the "alcohol-inducible" form of cytochrome P-450 is capable of CCl4- but not CHCl3-activation.

Alanine Transaminase↗

PubMed1986

Induction of cytochrome P-450 by alcohols and 4-substituted pyrazoles. Comparison of structure-activity relationships.

A comparison was made between 4-substituted pyrazoles and short-chain alcohols as inducers of cytochrome P-450. A quantitative structure-activity analysis of the data led to the following equations: (I) Pyrazoles: Log 1/C = 0.85 (+/- 0.21) Log P + 1.93 (+/- 0.38), r = 0.970 (II) Alcohols: Log 1/C = 0.78 (+/- 0.14) Log P + 1.46 (+/- 0.13), r = 0.988 where C is the concentration that caused a 50% increase in cytochrome P-450, is the partition coefficient between octanol and water, and r is the correlation coefficient. The results suggest that induction of cytochrome P-450 by these compounds depends on hydrophobicity alone. Electronic and steric factors have insignificant roles.

Alcohols↗

PubMed1991

Comparison between cobalt and pyrazole in the increased expression of coumarin 7-hydroxylase in mouse liver.

The data in this report show that administration of both cobalt and pyrazole results in an elevation in the amount of hepatic mRNA encoding for microsomal P45015 alpha/P450Coh, an increase in the amount of P450Coh protein, and an activation of COH and to a lesser extent testosterone 15 alpha-hydroxylase in two inbred strains of mice. Considerable quantitative differences between the two compounds and the two mouse strains in the response suggest that the effects of cobalt and pyrazole are mediated, at least partly, through different mechanisms. It is of interest that human hepatic COH resembles very closely that in the mouse liver.

Animals↗

PubMed1988

4-Amino-3-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)-5-pyrazole-carb oni trile. Synthesis and conversion into a sugar-blocked 5,7-disubstituted formycin analog.

The title compound, a potential intermediate to protected C-nucleoside analogs related to formycin A, was synthesized via a new route wherein 2,3,5-tri-O-benzyl-1-O-p-nitrophenyl)-D-ribofuranose was converted to 2,5-anhydro-3,4,6-tri-O-benzyl-D-allonic acid, and further transformed into 4-(tert-butyloxycarbonyl)-5-ethoxycarbonyl-3-(2,3,5-tri-O-benzyl-beta-D- ribofuranosyl)pyrazole. After amidation and dehydration to form the 4-(tert-butyloxycarbonyl)-5-pyrazolecarbonitrile, acidolysis followed by a Curtius-type sequence afforded the 4-amino-5-pyrazole-carbonitrile nucleoside. Treatment of the latter with nitrous acid and copper chloride in a Sandmeyer-type reaction gave a diazonitrile rather than a chloronitrile. Attempts to convert either the aminonitrile or the diazonitrile to 5,7-diamino-3-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrazolo[4,3-d] pyrimidine (5-aminoformycin A) by condensation with guanidine or N,N-dimethylguanidine were unsuccessful. Condensation of the aminonitrile with carbon disulfide in pyridine provided access to the formycin system in the form of 3-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine-5,7 - dithione.

Antibiotics, Antineoplastic↗

PubMedDate not supplied

Effects of pyrazole on the voluntary consumption of ethanol, water and solid food in UChA and UChB rats.

The effect of pyrazole (35 or 70 mg/kg IP) on the voluntary consumption of ethanol, water and solid food was studied in UChA (genetically low ethanol consumer) and UChB (genetically high ethanol consumer) rats of both sexes, under a free choice of 10% v/v ethanol solution, distilled water and solid food. the data were analyzed according to the method previously proposed for recognizing the specific effect on appetite-satiety of ethanol. The effect of pyrazole in UChB rats correlated with the pattern of specific effects on appetite-satiety for ethanol. The only effect observed in UChA rats was a decrease in the intake of solid food and total water. No significant sex differences were observed.

Alcohol Drinking↗

PubMed2004

Synthesis, antimicrobial activity and molecular modeling studies of halogenated 4-[1H-imidazol-1-yl(phenyl)methyl]-1,5-diphenyl-1H-pyrazoles.

During the course of our studies in the azole antifungals area, we synthesized a number of 1,5-disubstituted 4-[1H-imidazol-1-yl(phenyl)methyl]-1H-pyrazoles, analogues of bifonazole. 1,5-Diphenyl-1H-pyrazole 3 showed weak antimycotic and antibacterial activities in vitro against Candida albicans, Cryptococcus neoformans and Staphylococcus aureus. In order to increase these properties, given that the halo substitution was found to be capable of enhancing antifungal effects, we prepared a series of fluoro and chloro derivatives of 3. The microbiological evaluation carried out on newly synthesized compounds included in vitro assays for antifungal, antibacterial and antimycobacterial activities. Among the tested compounds, some dichloro and trichloro-derivatives showed interesting antimicrobial properties. In particular, compounds 10j,k,l produced inhibitory effects against pathogen representatives of yeast (C. albicans, C. neoformans) and Gram positive bacteria (S. aureus) similar or superior to those of bifonazole. In addition, their activity against Mycobacterium tuberculosis was superior to that of clotrimazole and econazole, which were used as reference drugs. The replacement, in these compounds, of chlorine with fluorine atoms led to inactive derivatives. Docking studies were carried out on the most active compounds, in order to rationalize the pharmacological results.

Anti-Bacterial Agents↗

PubMed2004

Synthesis of [O-methyl-11C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide: a potential PET ligand for CB1 receptors.

Synthesis and in vitro evaluation of [O-methyl-(11)C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide ([(11)C]-1), a potential imaging agent for CB(1) receptors using PET is described. 1-(2-Chlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (5), the precursor for radiolabeling, was synthesized from 4-OTBDPS-propiophenone (2) in five steps with 30% overall yield. The reaction of alcohol 5 with [(11)C]MeOTf at 60 degrees C afforded [(11)C]-1 with an average radiochemical yield of 14.5% (EOS) and >2000 Ci/mmol specific activity. The radiotracer was found to selectively label CB(1) receptors in slide-mounted sections of postmortem human brain containing prefrontal cortex as demonstrated by in vitro autoradiography using phosphor imaging.

Autoradiography↗

PubMed2004

The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.

4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.

Enzyme Inhibitors↗

PubMed2004

3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors.

A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 microM and COX-2: 1.2 microM).

Cyclooxygenase 1↗

PubMed2005

Synthesis and biological evaluation of novel steroidal pyrazoles as substrates for bile acid transporters.

A series of novel steroidal pyrazoles was synthesized as substrates for bile acid transporters to explore their potential as drug carriers. The selected pyrazole fused bile acids were further conjugated with drugs and drug surrogates. Their in vitro transport activities were evaluated in human ileal bile acid transporter (hIBAT) and human liver bile acid transporter (hLBAT) expressing Chinese hamster ovary (CHO)-cells and Xenopus laevis oocytes. The results of synthetic efforts and transporter assays studies are described herein.

Animals↗

PubMed2005

Synthesis and antibacterial activity of a novel series of DNA gyrase inhibitors: 5-[(E)-2-arylvinyl]pyrazoles.

The 2-arylvinyl moiety in 1-(3-chlorophenyl)-3-(4-piperidyl)-5-[(E)-2-(5-chloro-1H-indol-3-yl)vinyl]pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, was transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. Many of the 5-[(E)-2-arylvinyl]pyrazoles synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates of gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.

Anti-Bacterial Agents↗

PubMed2005

Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists.

A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K(i)=1 nM) and selectivity for the A(2B)-AdoR versus A(1), A(2A), and A(3)-AdoRs (A(1)/A(2B), A(2A)/A(2B), and A(3)/A(2B) selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.

Adenosine A2 Receptor Antagonists↗

PubMed2006

Design, synthesis, and preliminary biological evaluation of novel ethyl 1-(2'-hydroxy-3'-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate.

We synthesized a series of novel small molecules, ethyl 1-(2'-hydroxy-3'-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives 3a-3o, by the reaction of ethyl 3-aryl-1H-pyrazole-5-carboxylate with 2-aryloxymethylepoxide in the presence of potassium carbonate at refluxing in acetonitrile in moderate or excellent yields. We investigated the effects of all the compounds on A549 cell growth. The results showed that 15 compounds could suppress A549 lung cancer cell growth. Among them, compound 3i was the most effective small molecule in inhibiting A549 cell growth. Compound 3f might most effectively induce A549 cell differentiation. Compound 3g remarkably induced cellular vacuolation.

Antineoplastic Agents↗

PubMed2006

5-Heteroatom substituted pyrazoles as canine COX-2 inhibitors. Part III: molecular modeling studies on binding contribution of 1-(5-methylsulfonyl)pyrid-2-yl and 4-nitrile.

The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.

Animals↗

PubMed2006

Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues.

The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2'-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile.

Animals↗

PubMed2004

Biological evaluation of novel Pt(II) and Pd(II) complexes with pyrazole-containing ligands.

The new platinum (II) and palladium (II) complexes (2-4) with ligands 5-(2-hydroxyphenyl)-1,3-dimethyl-4-(dimethoxy)phosphonyl-1H]-pyrazole (1a) and 5-(2-hydroxyphenyl)-1,3-dimethyl-4-methoxycarbonyl-1H]-2-pyrazole (1b) were screened in a search for novel anticancer agents. Thus, alkylating activity, cytotoxicity, ability for induction of apoptosis and binding to DNA were tested. The cis-[Pt(1b)2Cl2] complex (3b) was the most potent alkylating agent in a Preussmann test, in comparison with the other test compounds and cis-platin. The highest cytotoxicity against the HL-60 and NALM-6 leukemia cell lines was observed for complexes 3b and 4b (trans-[Pd(1b)2Cl2]), although the extent of the effect was lower relative to cis-platin. Moreover, both complexes were remarkably less toxic to human umbilical vein endothelial cells (HUVECs) with IC50 values of 3b 14 and 20 times higher than that ones for HL-60 and NALM-6 cells, respectively. Complexes 3b and 4b induced caspase-3 activity. Apoptosis occurred in a strictly dose-dependent manner and required only low concentrations of 4b. However, compounds 3b and 4b showed lower binding affinity to double-stranded DNA than cis-platin.

Cell Line, Tumor↗