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PubMed2004

Synthesis of 4,5-diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors.

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus COX-1 enzyme.

Crystallography, X-Ray↗
PubMed2005

A novel route to fully substituted 1H-pyrazoles.

A novel one-step synthesis route to fully substituted pyrazol-4-ols is reported. This simple yet nonobvious method for the construction of pyrazol-4-ols by the condensation-fragmentation-cyclization-extrusion reactions of thietanones with 1,2,4,5-tetrazines is reported. All of the elements of the thietanone except its sulfur are incorporated in these novel products.

Enzyme Inhibitors↗
PubMed1998

Pyrazole-inducible proteins in DBA/2 mouse liver bind with high affinity to the 3'-untranslated regions of the mRNAs of coumarin hydroxylase (CYP2A5) and c-jun.

An important mechanism in the up-regulation of cytochrome P-450 2A5 (CYP2A5, coumarin hydroxylase, Coh) is the stabilization of the corresponding mRNA; some evidence suggests that proteins binding to CYP2A5 mRNA may be involved in this stabilization. Here we report that pyrazole, a well known inducer of CYP2A5 and stabilizer of its message, enhances the binding of a set of proteins to 32P-labelled 3'-untranslated region (3'UTR) of CYP2A5 to give 32P-labelled bands of apparent molecular mass 37/39, 45/48 and 70/72 kDa after UV cross-linking/RNase cleavage; in addition, we found different proteins binding to other parts of CYP2A5 mRNA. The 70/72 kDa bands are also formed with the 3'UTR of c-jun. The inducible proteins are found in different cellular subfractions at different concentrations, with a maximum of five-fold induction of binding activity in microsomes. When a gel-mobility-shift assay was combined with UV cross-linking to resolve different pyrazole-inducible RNA-protein complexes into single RNA-binding protein bands, the smallest complex contained a double band of 37/39 kDa, 45/48 kDa bands, 70/72 kDa bands, and additional weaker bands at higher molecular masses (around 120 kDa). This composition was found also for all other complexes detected by gel-mobility-shift assay; occasionally, bands at higher molecular masses were also observed. The proteins of the smallest complex might therefore represent a core with which other proteins interact to build up larger complexes. Binding of proteins 37/39 kDa and 70/72 kDa was located to a 20-base loop and adjacent sequences in a 70 nt AU-rich region of the 3'UTR of the CYP2A5. Based on our previous evidence, this 70-nt sequence may play an important role in the stabilization and processing of the message.

Animals↗
PubMed1994

Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing.

A major constitutive enzyme in the liver of the uninduced rat is cytochrome P450-2E1. This isozyme has been shown to metabolize a number of carcinogens, including low molecular weight nitrosamines and a number of compounds normally regarded as non-mutagenic in the Ames test, e.g. aniline, urethane and benzene. Using the standard induction procedures [Aroclor 1254 or a combination of phenobarbitone (PB) and beta-naphthoflavone (beta-NF)] the level of CYP2E1 in rat liver is actually suppressed and it has been suggested that this may account for the negative findings with these compounds in the Ames test. S9 fractions were prepared from rats pre-treated with pyrazole or ethanol (inducers of CYP2E1) and then used in the Ames test (or pre-incubation modification) with urethane, acetaminophen, aniline, benzene, procarbazine and N-nitrosopyrrolidine. Both pyrazole and ethanol induced S9 were superior to PB/beta-NF-S9 and uninduced-S9 for the activation of N-nitrosopyrrolidine, a known CYP2E1 substrate. However, there was no evidence of mutagenic activity with urethane, aniline, benzene, procarbazine or acetaminophen. As these compounds have demonstrated genotoxicity in vivo, additional important metabolic pathways must be required which are not present in rat liver S9 fraction.

Animals↗
PubMed2000

Supramolecular structure of 1H-pyrazoles in the solid state: a crystallographic and ab initio study.

The secondary structure of 1H-unsubstituted pyrazole derivatives bearing only one hydrogen donor group and one or more acceptor groups has been analyzed in terms of some descriptors representing the substituents at C3 and C5. The substituent at C4 appears to affect mainly the tertiary or quaternary structure of these compounds. The proposed semi-quantitative model, which explains most hydrogen-bonded motifs as a combination of the effects of substituents at C3 and C5, has also been examined as a function of the steric and polarizability effects of these substituents represented by molar refractivity. The model also applies to other five-membered rings (1,2,4-triazoles, 1,2,4-diazaphospholes and 1,2, 4-diazaarsoles). Furthermore, ab initio calculations at RHF/6-31G* have been performed to discover the relative stability of three of the four hydrogen-bond patterns displayed by several symmetrical pyrazoles (dimers, trimers, tetramers). The fourth motif, catemers, has only been discussed geometrically.

Crystallography, X-Ray↗
PubMed1991

Increased oxidation of dimethylnitrosamine in pericentral microsomes after pyrazole induction of cytochrome P-4502E1.

The cytochrome P-450IIE1 (CYP2E1) isozyme activates several toxins and procarcinogens. Recent studies employing immunohistochemical and immuno-analysis techniques have shown that this isozyme is predominantly localized in the pericentral zone of the liver acinus. Experiments were conducted to evaluate whether microsomes isolated from the pericentral region of the liver display elevated catalytic activity towards effective substrates for CYP2E1 such as dimethylnitrosamine (DMN) as compared with periportal microsomes. Rats were treated with pyrazole to induce CYP2E1 and hepatocytes prepared from periportal or pericentral zones of the livers by the digitonin-collagenase procedure. Microsomes isolated from these hepatocytes had similar total P-450 contents; however, the microsomes from the pericentral hepatocytes displayed an increased DMSO binding spectrum suggesting an increased content of CYP2E1. Low Km DMN demethylase activity (but not high Km activity) as well as the oxidation of aniline and p-nitrophenol were 2- to 3-fold higher in pericentral compared to periportal microsomes. The oxidation of DMN by both microsomal preparations, as well as the increased rates obtained with the pericentral microsomes, was sensitive to inhibition by carbon monoxide as well as to other CYP2E1 substrates such as ethanol, pyrazole, or 4-methylpyrazole. Anti-CYP2E1 IgG inhibited the oxidation of DMN by both microsomal preparations 75% to 85% and prevented most of the increase found with the pericentral microsomes. Oxidation of aniline and p-nitrophenol was elevated in pericentral hepatocytes compared with periportal hepatocytes to the same extent as in the isolated microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Non-specific prolongation of the effects of general depressants by pyrazole and 4-methylpyrazole.

The liver alcohol dehydrogenase inhibitors, pyrazole and 4-methylpyrazole, have been tested for their ability to prolong drug-induced sleep times in mice. Both drugs (at 1 mmol kg-1 i.p.) prolonged the duration of loss of righting reflex following chloral hydrate, pentobarbitone, barbitone, temazepam and halothane, but not diethyl ether. This suggests that the effects of these pyrazoles are not specific to the inhibition of liver alcohol dehydrogenase.

Animals↗
PubMed2002

N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor.

In superior cervical ganglion neurons, N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) competitively antagonizes the Ca(2+) current effect of the cannabinoid (CB) agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), and behaves as an inverse agonist by producing opposite current effects when applied alone. In contrast, in neurons expressing CB1 with a K-->A mutation at residue 3.28(192) (i.e., K3.28A), SR141716A competitively antagonizes the effects of WIN55212-2, but behaves as a neutral antagonist by producing no current effects itself. Receptor modeling studies suggested that in the CB1 inactive (R) state, SR1417A16A stabilizes transmembrane helix 6 in its inactive conformation via aromatic stacking with F3.36/W6.48. In this binding site, SR141716A would exhibit higher affinity for CB1 R due to a hydrogen bond between the SR141716A C3 substituent and K3.28(192), a residue available to SR141716A only in R. To test this hypothesis, a "mutant thermodynamic cycle" was constructed that combined the evaluation of SR141716A affinity at WT CB1 and K3.28A with an evaluation of the wild-type CB1 and K3.28A affinities of an SR141716A analog, 5-(4-chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole (VCHSR), that lacks hydrogen bonding potential at C3. Binding affinities suggested that K3.28 is involved in a strong interaction with SR141716A in WT CB1, but does not interact with VCHSR. Thermodynamic cycle calculations indicated that a direct interaction occurs between the C3 substituent of SR141716A and K3.28 in WT CB1. Consistent with these results, VCHSR acted as a neutral antagonist at WT CB1. These results support the hypothesis that hydrogen bonding of the SR141716A C3 substituent with K3.28 is responsible for its higher affinity for the inactive R state, leading to its inverse agonism.

Binding Sites↗
PubMed1977

Effect of alcohol on the heme and porphyrin synthesis interaction with phenobarbital and pyrazole.

The effect of alcohol in addition with respectively phenobarbital and pyrazole on the heme porphyrin synthesis in the liver of male rats was studied. After a single dose of 2 g alcohol/kg p.o. the activity of the delta-aminolevulinic acid synthetase (ALA synthetase) in the liver of starving rats increased 2- to 3-fold within 3 h. The porphyrin concentration in the liver of these animals was increased maximally by 75%. The activity of the delta-aminolevulinic acid dehydratase (ALA dehydratase), of the microsomal monoxygenase and of the concentration of cytochrome P-450 and ATP in the liver were not altered. A previous injection of pyrazole (6 mumol/kg) could abolish the inducing effect of alcohol on the ALA synthetase. The inducing effect of alcohol was increased by a previous injection of phenobarbital (80 mg/kg). The activity of the microsomal monoxygenase and the concentration of cytochrome P-450 was not altered by administration of an 8% alcohol solution instead of drinking water. The activity of the ALA synthetase in the liver of these animals was increased 3- to 4-fold only when they starved before sacrifice. In fed animals the activity of this enzyme was in the range of the control animals. The increase of the cytochrome P-450 concentration in the liver after 80 mg phenobarbital sodium/kg was lowered by alcohol. The experiments show that alcohol differs from other known porphyrinogenic agents. An alteration of the cytochrome P-450 concentration could not be demonstrated as the cause of the induction of the ALA synthetase. The observed porphyrinogenic effect is not caused by alcohol itself by either by its metabolites or by the changes of the liver metabolism caused by the effect of alcohol on the NAD/NADH ratio.

5-Aminolevulinate Synthetase↗
PubMed2006

Synthesis and evaluation of N-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1H-indole-carboxamides as cholecystokinin antagonists.

The structure-activity relationship optimization of the pyrazoline template 3a resulted in novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides 4a-4e. These non-peptidal CCK ligands have been shown to act as potent CCK1 ligands in a [125]I-CCK-8 receptor binding assay. The best amides (4c and 4d) of this series displayed an IC50 of 20/25 nM for the CCK1 receptor. In a subsequent in-vivo evaluation using various behaviour pharmacological assays, an anxiolytic effect of these novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides was found at high doses in the elevated plus-maze. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.33/0.41 mg kg(-1) was determined for amide 4c/4d and the antidepressant effect had a magnitude comparable to desimipramine.

Amides↗
PubMed1997

Cytoprotective effects of 4,6-bis(1H-pyrazol-1-yl)pyrimidine and related compounds on HCI.ethanol-induced gastric lesions in rats.

Bis(1H-pyrazol-1-yl)- and bis(1H-imidazol-1-yl)pyrimidines were synthesized and evaluated for cytoprotective effects. Among them, 4,6-bis(1H-pyrazol-1-yl)pyrimidine (3) showed a potent inhibitory effect on the HCl.ethanol-, ethanol-, and water immersion stress-induced gastric lesions in rats, and a very low acute toxicity. One of the major factors responsible for the cytoprotective effects of 3 is the increase in the bicarbonate secretion. This compound appears to be a promising cytoprotective drug for the treatment of gastric mucosal ulcers.

Animals↗
PubMed2003

Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents.

Several 1,3,4-trisubstituted pyrazole derivatives were synthesized and screened for their cytotoxic effect in a primary 3 tumor cell line test at 10(-4) M drug concentration. Compounds 19 and 20 reduced the growth of one or more of these cell lines to less than 32% and escalated up to evaluation in the full panel of 60 human tumor cell lines at a minimum of 5 concentrations at 10 fold dilutions. Compound N'-(1-[1-[4-nitrophenyl]-3-phenyl-1H-pyrazol-4-yl]methylene)-2-chlorobenzohydrazide 19 proved to be the most active of these derivatives with full panel median growth inhibition (GI50), total growth concentration (TGI) and median lethal concentration (LC50) mean graph mid-point (MG-MID) of 3.79, 12.5 and 51.5 microM, respectively. In addition, compounds 19, 39, 40, 41, 43, 45, 47 were tested for their antiangiogenic properties by testing their ability to inhibit human umbilical vein endothelial cells (HUVECs) proliferation, cord formation and migration in response to chemoattractant. 3-Acetyl-2-(1-(4-nitrophenyl)-3-phenylpyrazol-4-yl)-5-(4-pyridyl)-1,3,4-oxadiazoline 39 showed significant antiangiogenic profile at non-cytotoxic doses, with HUVEC proliferation inhibition IC50 of 7.60 microM, chemotaxis IC50 of 0.86 microM and was superior to the reference celecoxib 2 in both tests. Furthermore, in contrary to the references TNP-470 and celecoxib, all the tested compounds interfered with the migratory function of HUVECs in response to vascular endothelium growth factor (VEGF) rather than the endothelial cells proliferation.

Angiogenesis Inhibitors↗
PubMed2006

Synthesis, biological evaluation and 3D-QSAR of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase A inhibitors.

The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10(-8) - 9.0 x 10(-9)M range. Moreover, it should be pointed out that for most of them a high IC(50) > or = 10(-9)M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000-16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers. The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.

Animals↗
PubMed1975

The treatment of ethylene glycol toxicosis with pyrazole.

Rats and dogs were protected from the effects of lethal doses of ingested ethylene glycol (EG) with pyrazole (P), an inhibitor of liver alcohol dehydrogenase. Rats given 1.35 ml/100 g of EG followed by 2.2 mmol/kg of P i.p. at 6 and 30 hours postingestion survived. Untreated control animals died. Dogs were given either 10.0 or 12.5 ml/kg of EG and treatment was begun 6 hours later. The control treatment consised of NaHC03 administered i.v. according to the calculated base deficit, B-complex vitamins with ascorbic acid, hydrocortisone, and 5 per cent glucose in water. The addition postexposure to this treatment of 0.9 mmol/kg of P and 0.5 mmol/kg of P at 6 and 30 hours, respectively, constituted the experimental therapy. In summary: with 10 ml/kg of EG, no P, 2 of 5 dogs survived; 12.5 ml/kg of EG, no P, 0/1; 10 ml/kg of EG plus P, 9/11; 12.5 ml/kg of EG plus P, 12/22. Dogs that succumbed had large numbers of oxalate crystals in their kidneys at necropsy. The surviving dogs had few oxalate crystals in their kidneys at the time of unilateral nephrectomy (2 weeks postexposure) or necropsy (30 days postexposure). Several clinical factors were identified as useful prognostic indicators in the treatment of EG poisoning. The results suggested that pyrazole, despite its marked toxicity, may be of clinically significant value in the treatment of ethylene glycol poisoning when therapy is initiated withing 6 hours of exposure.

Animals↗
PubMed1975

[Steroidal heterocyclic compounds: [16,15-c]-pyrazole derivatives of estradiol and of estrone].

Condensation between ethyl formate and estradiol 16-keto derivatives, in which the 17beta-hydroxyl groups had been protected as tetrahydropyranyl ethers, produced the corresponding 15-hydroxymethylene compounds. These, by cyclization with hydrazine, gave the [16,15-c]-pyrazole derivatives. Further reactions, such as hydrolysis, etherification and chromic oxidation, afforded many differently substituted [16,15-c]-pyrazoles of the estradiol and estrone series.

Chemistry, Pharmaceutical↗
PubMed1990

Researches on antiinflammatory agents. Studies on some new 3-(pyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-ones and -quinazolin-4(3H)-ones.

Following our research on analgesic and antiinflammatory active compounds containing the pyrazole nucleus, a number of 3-(pyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-ones and quinazolin-4(3H)-ones was synthetized and tested. The results of tests for analgesic, antiexudative and antioedema activities, as well as for induction of lesion in the gastric mucosa, are reported and discussed.

Animals↗
PubMed1987

[Acetylsalicylic acid and pyrazole allergy or pseudo-allergy?].

In a multicentric study by the European Study Group of Drug Allergy, 69 patients suffering from immediate type reaction after the intake of non-steroidal antiphlogistica were examined with regard to allergy or pseudo-allergy. Apart from the scratch test on the original substance, we performed cutaneous tests with salicyloyl and pyrazol conjugates, and determined IgE and IgG by means of a modified RAST method. There were 3 groups to be distinguished: (1) "intolerance" reaction of the aspirin type as a pseudo-allergic reaction (15 cases); (2) true IgE-mediated allergy (16 cases); (3) pyrazol "idiosyncrasy" (33 cases). 5 patients showed a combination of the three pathomechanisms.

Aspirin↗