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PubMed1986

Rat liver microsomal induction of the oxidation of drugs and alcohols, and sodium dodecyl sulfate-gel profiles after in vivo treatment with pyrazole or 4-methylpyrazole.

Studies were carried out to characterize and compare the effects of pyrazole and 4-methylpyrazole, potent inhibitors of alcohol dehydrogenase, on microsomal oxidation of a variety of drugs and alcohols. Whereas pyrazole treatment of rats (200 mg/kg b.wt./day for 2 days) resulted in an enrichment of a cytochrome P-450 isozyme with a molecular weight of about 52,000 on sodium dodecyl sulfate gels, 4-methylpyrazole treatment resulted in increased amounts of two or three P-450 isozymes, one of which appeared to be similar to the isozyme increased by pyrazole. The qualitative induction of two or three isozymes of P-450 as shown by sodium dodecyl sulfate-gel electrophoresis correlates with a 2-fold increase in total content of P-450 by 4-methylpyrazole. Microsomes from the pyrazole-treated rats displayed increased activity (expressed per milligram of protein or per nanomole of P-450) with aniline, p-nitroanisole, dimethylnitrosamine (low-Km enzyme) and ethanol as substrates, but not with aminopyrine, ethoxycoumarin or dimethylnitrosamine (high-Km enzyme). A stereochemical preference for the (+)-2-butanol isomer over the (-)-isomer was also observed. Kinetic experiments indicated that the pyrazole treatment increased the Vmax for ethanol, aniline and (+)-2-butanol oxidation. These properties are similar to those found with microsomes from chronic ethanol-fed rats and suggest that, in rats, pyrazole and ethanol may induce similar isozymes of P-450, and that the former may serve as a convenient model for the latter. This comparable induction between ethanol and pyrazole is in contrast to results using imidazole, which has been reported by others not to induce an alcohol-preferring P-450 in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗

PubMed1994

Characterization of pyrazole and 4-methylpyrazole induction of cytochrome P4502E1 in rat kidney.

Pyrazole and 4-methylpyrazole induce cytochrome P4502E1 (P4502E1) in the liver. It is not known whether induction occurs in nonhepatic tissue such as kidney and lung. Rats were treated with saline, pyrazole or 4-methylpyrazole and assayed for the activity and content of P4502E1 and mRNA in liver, lung and kidney. Treatment with these agents resulted in increases in P4502E1 content as detected by immunoblots in liver and kidney, but not lung, microsomes. Oxidation of relatively specific substrates for P4502E1 was also significantly increased with liver and kidney microsomes after pyrazole or 4-methylpyrazole treatment. P4502E1 mRNA levels in liver, kidney and lung were not increased by treatment with pyrazole or 4-methylpyrazole. Associated with the induction of P4502E1 was an elevated production of reactive oxygen intermediates such as superoxide radical and H2O2 by kidney and liver, but not lung. microsomes. Lipid peroxidation induced by CCI4 was also increased with kidney microsomes after treatment with pyrazole or 4-methylpyrazole. Anti-P4502E1 IgG inhibited the increased oxidation of substrates and the increased production of H2O2 by the kidney microsomes found after treatment with pyrazole and 4-methylpyrazole. These results show that pyrazole and 4-methylpyrazole, which induce P4502E1 in liver, are also effective in inducing this enzyme in the kidney, whereas the lung is not sensitive to induction by these agents. The mechanism of induction of kidney P4502E1, similarly to that of liver, appears to reflect a post-transcriptional effect-probably stabilization of the protein against degradation.

Animals↗

PubMed1993

Evidence for identity of beta-pyrazolealanine synthase with cysteine synthase in watermelon: formation of beta-pyrazole-alanine by cloned cysteine synthase in vitro and in vivo.

The responsibility of cysteine synthase (EC 4.2.99.8) from watermelon (Citrullus vulgaris) for the formation of beta-(pyrazole-1-yl)-L-alanine, a non-protein amino acid specifically accumulated in Curcubitaceae plants, was confirmed in vitro and in vivo by the cloned cDNA on expression vectors, pCCS11 and pCEN1. The cDNA sequence derived from pCCS11, an expression vector driven by the lacZ promoter, was placed under the transcriptional control of strong T7 promoter of pET3d to yield an over-expression vector, pCEN1, in Escherichia coli. The concentration of the exogenous cysteine synthase protein was increased up to approximately 10% of the total soluble protein of E. coli cells by the expression of cDNA on pCEN1. beta-(Pyrazole-1-yl)-L-alanine was formed in vitro from O-acetyl-L-serine and pyrazole by the action of cysteine synthase expressed in E. coli carrying pCCS11 or pCEN1. To confirm the responsibility of cysteine synthase for the formation of beta-(pyrazole-1-yl)-L-alanine in vivo, the feeding experiments of pyrazole and serine or O-acetyl-L-serine were carried out using the transformed E. coli culture. beta-(Pyrazole-1-yl)-L-alanine was produced in vivo by feeding the substrates to the culture of E. coli carrying pCEN1. These results provide the confirming evidence that the cloned cysteine synthase of watermelon catalyzes the formation of beta-(pyrazole-1-yl)-L-alanine, indicating that beta-pyrazolealanine synthase is identical with cysteine synthase in Cucurbitaceae plants.

Base Sequence↗

PubMed1987

1,3-Dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols. A series of novel potential antipsychotic agents.

2-(Diethylamino)-N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl] acetamide (1) was recently found to have an antipsychotic-like profile in behavioral animal tests but, unlike clinically available antipsychotic agents, did not interact with dopamine receptors. Compound 1 was apparently metabolized to (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (2), which was both active in the behavioral animal tests and toxic. The synthesis and pharmacological evaluation of a series of 1,3-dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols are described in which the hydroxy and imine functionalities were selected as possible isosteric replacements for the amino and ketone groups of the earlier series. The initial target, 1,3-dimethyl-4-(iminophenylmethyl)-1H-pyrazol-5-ol (28), like known antipsychotics, reduced spontaneous locomotion in mice at doses that did not cause ataxia, and unlike known agents, it did not bind to D2 dopamine receptors in vitro. An examination of the SAR of related compounds indicated that maximal activity was obtained with analogues containing methyl groups at the 1- and 3-positions on the pyrazole ring and with a 3-chloro substituent on the phenyl ring. Replacement of the hydrogen atom of the imine moiety with various substituents led to loss of activity. Attempts to synthesize the 2-fluorophenyl compound analogous to 2 resulted in ring-closure to 1,3-dimethyl[1]benzopyrano[2,3-c]pyrazol-4-(1H)-one (65). 4-[(3-Chlorophenyl)iminomethyl]-1,3-dimethyl-1H-pyrazol-5-ol (41) was evaluated in additional tests. It inhibited conditioned avoidance responding in both rats and monkeys but, unlike available antipsychotic drugs, did not elicit dystonic movements in a primate model of antipsychotic-induced extrapyramidal side effects.

Animals↗

PubMed2006

Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: role of cytochrome P450 2E1 and 2A5.

The mechanisms by which alcohol causes liver injury are still not certain. Either LPS or CYP2E1 are considered independent risk factors involved in alcoholic liver disease, but mutual relationships or interactions between them are unknown. In the present study, the possible synergistic action of CYP2E1 and LPS in liver injury was investigated by evaluating the effects of pyrazole (inducer of CYP2E1), Chlormethiazole (CMZ), an inhibitor of CYP2E1, and CYP2E1-knockout mice. Mice were injected with pyrazole (150 mg/kg, ip) daily for 2 days, followed by LPS injection (4 mg/kg, ip). CMZ (50mg/kg, ip) was administered 15 h before and 30 min after LPS treatment, respectively. LPS-induced liver injury was enhanced by pyrazole, as indicated by pathological changes and increases in ALT and AST, and positive TUNEL staining. LPS-induced oxidative stress was also enhanced by pyrazole as indicated by increases in 4-hydroxy-2-nonenal and 3-nitrotyrosine adduct formation. CMZ protected against the pyrazole enhanced LPS liver injury and oxidative stress. CYP2E1 but also CYP2A5 were increased by the pyrazole/LPS treatment. CMZ decreased the elevated CYP2E1 activity by 90%, but CYP2A5 activity was also lowered (30%-50%). CYP2E1-knockout mice exhibited only minor liver injury after treatment with pyrazole/LPS, but wild-type mice exhibited severe liver injury. While no CYP2E1 was present in the CYP2E1 knockout mice, CYP2A5 activity was also lower. In conclusion, induction of CYP2E1 plays an important role in the enhancement of LPS liver injury by pyrazole, but some contribution by CYP2A5 cannot be excluded.

Alcohol Dehydrogenase↗

PubMed1995

Differences in teratogenic and toxic properties of alcohol dehydrogenase inhibitors pyrazole and 4-methylpyrazole in Drosophila melanogaster: I. ADH allozymes in variable genetic backgrounds.

Pyrazole and 4-methylpyrazole (4-MP) are effective inhibitors of alcohol dehydrogenase (ADH) activity in mammals both in vivo and in vitro. 4-MP has a tenfold higher inhibition specificity compared with pyrazole. Pyrazole proved a teratogenic compound in Drosophila melanogaster. Treatment of third instar larvae of D. melanogaster with pyrazole, in contrast with 4-MP, produced an increase in the number of dorsocentral and scutellar macrochaetae and wing-notches in the adult fly. A large difference in the penetrance of terata in males and females was observed. Similar effects were observed in flies lacking ADH molecules. The teratogenicity of pyrazole must be due to disturbance of processes other than ADH inhibition. Synergistic effects were observed between pyrazole and methoxyacetic acid (MAA), an in vitro inhibitor of sarcosine dehydrogenase activity. Each of these compounds, when fed to early third instar larvae, produced terata resembling the Notch mutant of D. melanogaster.

Acetates↗

PubMed1988

Pyrazole: preclinical reassessment.

Pyrazole (NSC-45410) is a low molecular weight, heterocyclic compound which has been considered for reevaluation in the clinic as a potential cytotoxic agent (Fig. 1). Discovered in 1893, pyrazole is best known as an inhibitor of liver alcohol dehydrogenase (ki = 0.2 uM), and as a result, has been used extensively in studies of alcohol metabolism. In 1960, pyrazole was identified as being active in preclinical antitumor models, which led to preliminary clinical testing. The early Phase I studies were not followed by disease specific Phase II trials, and the clinical activity of the drug has never been evaluated. This omission was noted by the National Cancer Institute's Project for the Review of Old Drugs (PROD), at which time it was also noted that pyrazole is selectively toxic to thyroid tissue in an animal model. Hence, interest in pyrazole was revived for two reasons: (a) failure to screen it for clinical activity in the 1960's, and (b) current interest in discovering drugs with selective toxicity to specific tissues for evaluation of their activity in malignancies arising in the target tissue. In this review, we summarize the evidence which has accumulated concerning pyrazole's potential role as an anticancer agent.

Animals↗

PubMed1985

Effects of pyrazole on nitrosodimethylamine demethylase and other microsomal xenobiotic metabolising activities.

Pyrazole administered to immature rats at one day or on four successive days prior to sacrifice increased a microsomal NDMAD with apparent Km 0.04 mM. Aniline hydroxylase activity was also increased by these treatments. Ethoxycoumarin deethylase and amino pyrine demethylase activities were not altered when animals were treated with pyrazole one day prior to sacrifice but were reduced to below control activity when animals were treated for four successive days. All microsomal mono-oxygenases were decreased when animals received a single administration of pyrazole four days prior to sacrifice and the cytochrome P-450 content of these microsomes was reduced by up to 50%. When microsomes from untreated animals or animals treated for four successive days were incubated with pyrazole in the presence of NADPH, cytochrome P-450 content decreased in a time dependent process to a limiting value. The effect was dependent on pyrazole concentration and saturable. These results suggest that pyrazole induces a cytochrome P-450 isoenzyme with high affinity for NDMA but also acts as a suicide inhibitor of the cytochrome.

Animals↗

PubMed1987

Increased sensitivity of the microsomal oxidation of ethanol to inhibition by pyrazole and 4-methylpyrazole after chronic ethanol treatment.

Pyrazole and 4-methylpyrazole, inhibitors of the oxidation of ethanol by alcohol dehydrogenase, also inhibit microsomal metabolism of ethanol. The inhibitory effectiveness of these agents was increased in microsomes isolated from rats treated chronically with ethanol as compared to microsomes from pair-fed controls or from rats treated with other cytochrome P-450 inducers such as phenobarbital or 3-methylcholanthrene. Pyrazole and 4-methylpyrazole produced type II binding spectra with all the microsomal preparations. However, there was an increased affinity (lower Ks value) for these agents by the microsomes from the ethanol-fed rats. A correlation between Ks values and inhibitory effectiveness against ethanol oxidation by the various microsomal preparations could be observed. This suggests that an increase in affinity, which may reflect the induction of an alcohol-preferring isozyme of cytochrome P-450, is responsible for the increased inhibitory effectiveness of pyrazole and 4-methylpyrazole towards ethanol oxidation by microsomes after chronic ethanol treatment. One difference between pyrazole and 4-methylpyrazole was the increased affinity and inhibitory effectiveness of the latter but not the former with microsomes from rats treated with 3-methylcholanthrene. This could be due to the ability of 4-methylpyrazole, compared to pyrazole, to interact with and induce several isozymes of cytochrome P-450. Pyrazole and 4-methylpyrazole are often utilized to evaluate ethanol metabolism by alcohol-dehydrogenase-dependent and -independent pathways. However, the sensitivity of microsomal ethanol oxidation to inhibition by these agents, especially after chronic ethanol treatment, would suggest that their use in this regard is complex and could tend to underestimate the contribution of the microsomal pathway towards the metabolic tolerance found after ethanol treatment.

Animals↗

PubMed1991

Inducibility of P450Coh by pyrazole and its derivatives.

Pyrazole and several of its derivatives increase the hepatic microsomal coumarin 7-hydroxylase to a variable extent. The strongest inducers are pyrazole itself and those derivatives which have a hydroxy group or a halogen at the 4-position of the molecule. The increase in coumarin 7-hydroxylase is due to an increase in the microsomal P450Coh and the corresponding mRNA. The increase of P450Coh by pyrazole and 4-hydroxypyrazole is selective because several other mono-oxygenase enzymes and the total P450 content are either not affected or even decreased. These include the testosterone 15 alpha-hydroxylase (P45015 alpha), a close structural analogue of P450Coh, which is induced only marginally by pyrazole and even decreased by 4-iodopyrazole, and P450ac which is decreased by pyrazole and 4-hydroxypyrazole. Introducing a methyl residue at the 4-position will alter the induction properties of the compound essentially bymaking it less selective for P450Coh. These results demonstrate the special selective action of pyrazole and some of its derivatives on the hepatic microsomal mono-oxygenase complex and the unique mode of regulation of the cytochrome P450Coh even within the same subfamily of cytochromes P450.

Animals↗

PubMed1979

Ethanol, disulfiram, and pyrazole: effects on interferon production in mice.

The effects of ethanol alone or combined with pyrazole or disulfiram were studied in reference to interferon production. Saline, ethanol (2 g/kg), pyrazole (2 mg/kg), or disulfiram (2 mg/kg) were injected, intraperitoneally, 3 hr after poly I:C, an interferon inducer. Drugs were administered either by a single injection, or twice daily for 7 days, and the mice were sacrificed 6 hr after poly I:C. Sera from mice were pooled, dialyzed, and assayed for interferon by the microplaque reduction method. Administration of ethanol alone reduced interferon production 76% and 66% after the single and the multiple injections, respectively. A similar inhibition of interferon occurred after either pyrazole or disulfiram, with a greater potency for pyrazole. Treatment with pyrazole prior to ethanol reduced interferon production further, but only after the 7-day schedule. All drugs tested affected cellular immunity as measured by interferon production. Moreover, reduced interferon production by these agents was associated with a loss of splenic lymphoid tissue, suggesting that ethanol, pyrazole, and disulfiram could affect susceptibility to viral infection.

Animals↗

PubMedDate not supplied

Inhibition of carcinogenicities of 1,2-dimethylhydrazine and azoxymethane by pyrazole.

Inhibitory effects of pyrazole on the carcinogenicities of 2 large-bowel carcinogens, 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM), were examined, because our previous study revealed that pyrazole completely inhibited the induction of mutations by these carcinogens in the host-mediated mutation assay. ICR male mice were treated subcutaneously once a week for 20 weeks either with DMH or with AOM. Pyrazole was given orally to mice 2 h before treatment with the carcinogen. Pathological examinations were conducted 36 weeks after the first treatment. Treatment with DMH or AOM alone induced colorectal and/or anal tumorigenic lesions in 92% (23/25) mice of the DMH group and 100% (22/22) mice of the AOM group. By contrast, none of the animals in the combined treatment groups (carcinogen + pyrazole) developed those tumors. On the other hand, 50% (13/26) of mice treated with DMH alone and 78% (18/23) of mice treated with AOM alone developed vascular tumors. Pretreatment of mice with pyrazole reduced the percentage of mice bearing this type of tumor to about 30% of that in the carcinogen group with either carcinogen. These results clearly show that pyrazole has the ability to inhibit carcinogenicities of DMH and AOM, especially for the colorectum and anus, and indicate that the inhibition studies of mutation induction in vivo provide a useful tool for the screening for inhibitors of the carcinogenicities of DMH and AOM.

1,2-Dimethylhydrazine↗

PubMed2005

Candidate PET radioligands for cannabinoid CB1 receptors: [18F]AM5144 and related pyrazole compounds.

INTRODUCTION: The mammalian brain contains abundant G protein-coupled cannabinoid CB(1) receptors that respond to Delta(9)-tetrahydrocannabinol, the active ingredient of cannabis. The availability of a positron emission tomography (PET) radioligand would facilitate studies of the addictive and medicinal properties of compounds that bind to this receptor. Among the known classes of ligands for CB(1) receptors, the pyrazoles are attractive targets for radiopharmaceutical development because they are antagonists and are generally less lipophilic than the other classes. METHODS: A convenient high-yield synthesis of N-(4-[(18)F]fluorophenyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxamide (AM5144) was devised by coupling the appropriate pyrazole-3-carboxyl chloride compound with 4-[(18)F]fluoroaniline. The labeled precursor was synthesized from 1-[(18)F]fluoro-4-nitrobenzene in 60% radiochemical yield for 10 min using an improved procedure involving sodium borohydride reduction with cobalt chloride catalysis. The product was purified by HPLC to give a specific activity >400 mCi/micromol and a radiochemical purity >95%, and a PET study was conducted in a baboon. RESULTS: Although the regional uptake of AM5144 in baboon brain was consistent with binding to cannabinoid CB(1) receptors, absolute uptake at <0.003% injected radioactivity per cubic centimeter was lower than the previously reported uptake of the radioiodinated pyrazole AM281. CONCLUSIONS: The relatively poor brain uptake of AM5144 and other pyrazole CB(1) receptor ligands is not surprising because of their high lipophilicity as compared with most brain PET radiotracers. However, for nine pyrazole compounds for which rodent data are available, brain uptake and calculated logP values are not correlated. Thus, high logP values should not preclude evaluation of radiotracers for targets such as the CB(1) receptor that may require very lipophilic ligands.

Aniline Compounds↗

PubMed1979

Histochemical and morphological evaluation of cerebral cortex of newborn rat in the course of joint ethanol and pyrazole administration.

The object of the study was the cerebral cortex of newborn rat. Tissue material was collected from the 2-nd to the 8-th hour after birth both from control animals and newborns whose mothers had been given both ethanol and pyrazole throughout gestation period, and also either ethanol alone or pyrazole. The drug were administered by gastric tube, in doses: ethanol 8.0 g/kg body weight, pyrazole 36 mg/kg body weight. Histochemical studies revealed variation in the intensity of reaction of the respiratory enzymes during examination of the cortex of newborns whose mothers had been fed with ethanol alone, or pyrazole alone. A strong inhibition of enzymatic reaction was observed in the examined cerebral cortex of newborns after a joint ethanol and pyrazole administration. Morphological studies showed an inhibition of maturing process of the cerebral cortex cells of animals treated with ethanol alone, whereas the cerebral cortex of animals whose mothers had been given both ethanol and pyrazole, presented symptoms allowing to diagnose encephalitis congenita symptomatica.

Animals↗

PubMed2003

Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression.

Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.

Alanine Transaminase↗

PubMed1982

Pyrazole binding in crystalline binary and ternary complexes with liver alcohol dehydrogenase.

Pyrazole is a strong inhibitor of liver alcohol dehydrogenase in combination with oxidized coenzyme NAD+. We have studied three different complexes of the inhibitor with the enzyme by using crystallographic methods: (1) the binary complex with pyrazole to 3.2-A resolution, (2) the ternary ternary complex with NAD+-4-iodopyrazole to 2.9-A resolution. Crystals of the binary complex are isomorphous to the apoenzyme, and pyrazole binds to the active-site zinc atom in a way analogous to imidazole. Crystals of the two ternary complexes are isomorphous with the ternary alcohol dehydrogenase-NADH-dimethyl sulfoxide complex. One of the nitrogen atoms of the pyrazole ring is directly bound to the active-site zinc atom with a Zn-N bond distance of 2.1A. The other nitrogen atom is 2 A from the C4 atom of the nicotinamide ring of the coenzyme. The iodine atom in 4-iodopyrazole is located in the hydrophobic substrate cleft. The effect of substitutions on the pyrazole ring are discussed in relation to the structure of the active site and substrate pocket. Pyrazole derivatives with long alkyl chains bound in the 4 position are outstanding inhibitors, and this property is related to the topography of the hydrophobic substrate cleft. The conformation of the oxidized coenzyme in the ternary complexes is essentially the same as that of the reduced coenzyme NADH in the NADH-dimethyl sulfoxide complex.

Alcohol Dehydrogenase↗

PubMed2000

Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists.

We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ERalpha than on the ERbeta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERalpha-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERalpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERalpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERalpha. It also activates gene transcription only through ERalpha. Thus, this compound represents the first ERalpha-specific agonist. We investigated the molecular basis for the exceptional ERalpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ERalpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERalpha has a smaller residue than ERbeta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERalpha.

Binding, Competitive↗

PubMed1979

Alkylating nucleosides. 2. Synthesis and cytostatic activity of bromomethylpyrazole and pyrazole nitrogen mustard nucleosides.

Glycosylation of ethyl 3(5)-(bromomethyl)pyrazole-5(3)-carboxylate (3) and 3(5)-(bromomethyl)pyrazole-5(3)-carboxamide (4) with poly-O-acetylated sugars via an acid-catalyzed fusion method afforded the corresponding ethyl 3-(bromomethyl)pyrazole-5-carboxylate and 3-(bromomethyl)pyrazole-5-carboxamide substituted nucleosides 5 and 7, respectively. In some cases, the positional isomers 6 and 8 were also obtained. Treatment of 5 and 7 with methanolic ammonia gave the deprotected 3-(aminomethyl)pyrazole-5-carboxamide nucleosides 9. Reaction of 3--5 and 7 with bis(2-chloroethyl)amine led to the corresponding pyrazole nitrogen mustards 10--13. All the bromomethylpyrazole nucleosides described showed significant cytostatic activity against HeLa cell cultures.

Antineoplastic Agents↗