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PubMed1986

(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanones . A series of novel potential antipsychotic agents.

(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (1) was found to have an antipsychotic-like profile in behavioral tests predictive of antipsychotic efficacy but, unlike available antipsychotic agents, did not bind in vitro to dopamine receptors. Upon further evaluation, 1 was found to cause clonic seizures in aged rodents. An examination of related structures revealed that 5-(substituted aminoacetamide) analogues of 1 shared this novel pharmacology and did not cause seizures. The synthesis and pharmacological evaluation of this series of compounds are described. Two compounds, 2-(diethylamino)acetamide (25) and 2-[[3-(2-methyl-1-piperidinyl)propyl]-amino]acetamide (38), were selected for examination in secondary tests. Like known antipsychotics both compounds reduced spontaneous locomotion in mice at doses that did not cause ataxia and inhibited conditioned avoidance selectively in both rats and monkeys. Unlike known antipsychotics neither 25 nor 38 elicited dystonic movements in haloperidol-sensitized cebus monkeys, a primate model of antipsychotic-induced extrapyramidal side effects. Biochemical studies indicated that these compounds act via a nondopaminergic mechanism. Neither 25 nor 38 bound to dopamine receptors in vitro or caused changes in striatal dopamine metabolism in vivo. In addition, they did not raise serum prolactin levels as do known antipsychotics. Although adverse animal toxicological findings have precluded clinical evaluation of these agents, the present results indicate that it is possible to identify at the preclinical level nondopaminergic compounds with antipsychotic-like properties.

Animals↗
PubMed1979

Synthesis and antileukemic activities of furanyl, pyranyl, and ribosyl derivatives of 4-(3,3-dimethyl-1-triazeno)imidazole-5-carboxamide and 3-(3,3-dimethyl-1-triazeno)pyrazole-4-carboxamide.

From the reaction of silylated 4-(3,3-dimethyl-1-triazeno)imidazole-5-carboxamide (DTIC, 5) and 3-(3,3-dimethyl-1-triazeno)pyrazole-4-carboxamide (DTPC, 9) with 2-chlorotetrahydrofuran, we have isolated in both cases a single tetrahydrofuran-2-yl derivative. However, when silylated DTPC was reacted with 2-chlorotetrahydropyran, two tetrahydropyran-2-yl compounds were obtained, and these were shown to be positional isomers on the basis of 1H NMR and UV data. These furanyl and pyranyl derivatives were tested for antileukemic activity (L-1210, in vivo) and the results were compared with the results obtained for the corresponding ribosyl derivatives of DTIC and DTPC.

Animals↗
PubMed1982

Synthesis and antiinflammatory activity of hexahydrothiopyrano[4,3-c]pyrazoles and related analogues.

A series of novel hexahydrothiopyrano[4,3-c]pyrazoles and related analogues were prepared and tested for antiinflammatory activity by using the mouse active Arthus reaction and the delayed hypersensitivity skin reaction in guinea pigs as primary screens. The compounds of most interest, 18 and 28, were further tested in a model of adjuvant-induced arthritis; in this system, both compounds were active when dosed intraperitoneally but failed to produce significant activity when dosed orally at subtoxic doses.

Animals↗
PubMed2001

The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice.

This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.

Acetamides↗
PubMed2002

Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate.

We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.

Animals↗
PubMed2003

Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.

In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral conditions and instability under acidic conditions. The instability of HET0016 in acidic conditions is due to the N-hydroxyformamidine moiety, which is considered to be essential for the potent and selective activity seen in our previous study. The activity was maintained when the N-hydroxyformamidine moiety was replaced by an imidazole ring (3a; IC(50) = 5.7 +/- 1.0 nM), but this was associated with a loss of selectivity for cytochrome p450s (CYPs). However, other azole derivatives such as isoxazole derivative 23 (IC(50) value 38 +/- 10 nM) and pyrazole derivative 24 (IC(50) value 23 +/- 12 nM) showed potent and selective activities with improved stability.

Arachidonic Acid↗
PubMed2003

Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.

3T3 Cells↗
PubMed2004

Synthesis and selective inhibitory activity of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives against monoamine oxidase.

A novel series of 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives 1-12 have been synthesized and investigated for the ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The new synthesized compounds 1-12 proved to be more reversible, potent, and selective inhibitors of MAO-A than of MAO-B. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds, 6 and 11. The separated enantiomers were then submitted to in vitro biological evaluation while increasing their inhibitory activity and A selectivity. The (-)-6 enantiomer shows K(i(MAO-A)) = 2 nM and SI = 165 000, (+)-6 shows K(i(MAO-A)) = 6 nM and SI = 166 666, (-)-11 shows K(i(MAO-A)) = 4 nM and SI = 80 000, and (+)-11 shows K(i(MAO-A)) = 7 nM and SI = 38 571.

Animals↗
PubMed2005

Bioisosteric replacements of the pyrazole moiety of rimonabant: synthesis, biological properties, and molecular modeling investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists.

Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.

Administration, Oral↗
PubMed2005

Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)- pyrazole derivatives.

A novel series of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). All the synthesized compounds show high activity against both the MAO-A and the MAO-B isoforms with Ki values between 27 and 4 nM and between 50 and 1.5 nM, respectively, except for a few derivatives whose inhibitory activity against MAO-B was in the micromolar range. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation. The selectivity of the (-)-(S)-1 enantiomer against MAO-B increases twice and a half, while the selectivity of the (-)-(S)-4 enantiomer against MAO-A triples. Both the MAO-A and MAO-B isoforms respectively of the 1O5W and 1GOS models deposited in the Protein Data Bank were considered in the computational study. The docking study was carried out using several computational approaches with the aim of proposing possible binding modes of the MAO enantioselective compounds 1 and 4.

Binding Sites↗
PubMed2004

Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo.

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.

Allosteric Regulation↗
PubMed2005

(6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells.

A series of (6,7-dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines has been optimized to preserve both potent kinase inhibition activity against the angiogenesis target, the receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to improve the broad tumor cell antiproliferative activity of these compounds. This series culminates in the discovery of 17 (JNJ-10198409), a compound with anti-PDGFR-beta kinase activity (IC(50)=0.0042 microM) and potent antiproliferative activity in six of eight human tumor cell lines (IC(50) < 0.033 microM).

Antineoplastic Agents↗
PubMed2006

Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-beta type I receptor inhibitor.

Inhibitors of transforming growth factor beta (TGF-beta) type I receptor (ALK5) offer a novel approach for the treatment of fibrotic diseases such as renal, hepatic, and pulmonary fibrosis. The optimization of a novel phenylpyridine pyrazole series (1a) led to the identification of potent, selective, and orally active ALK5 inhibitors. The cellular potency and pharmacokinetics profiles of these derivatives were improved and several compounds presented antifibrotic activity when orally administered to rats in an acute liver model of dimethylnitrosamine- (DMN-) induced expression of collagen IA1 mRNA, a major gene contributing to excessive extra cellular matrix deposit. One of the most potent ALK5 inhibitors identified in this chemical series, compound 13d (GW788388), reduced the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). This compound significantly reduced the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis.

Activin Receptors, Type I↗
PubMed2006

1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.

The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.

Animals↗
PubMed2000

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.

Animals↗
PubMed2000

A combination of tandem amine-exchange/heterocyclization and biaryl coupling reactions for the straightforward preparation of phenanthro[9,10-d]pyrazoles.

The tandem amine-exchange/heterocyclization of enaminoketones is successfully applied to the regioselective preparation of a series of new 4,5-diarylpyrazoles by reaction of phenylhydrazine and several 3-N,N-(dimethylamino)-1,2-diarylpropenones. The comparison of a vast array of biaryl coupling procedures provides general, complementary approaches to new phenanthro[9,10-d]pyrazoles. The most efficient procedures for this final step in the construction of the tetracyclic system are based on a Stille-type tandem stannylation-biaryl coupling of o,o'-dihalogenated diarylpyrazoles and an hypervalent iodine-mediated nonphenolic oxidative coupling of nonhalogenated precursors.

Cyclization↗
PubMed2001

Regioselective synthesis of polysubstituted pyrazoles and isoxazoles.

A regioselective synthesis has been developed for the preparation of unsymmetrical 1,3,5-triaryl-4-alkylpyrazolines and -pyrazoles by treatment of alpha-benzotriazolyl-alpha,beta-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring. Reaction of alpha-benzotriazolyl-alpha,beta-unsaturated ketones with hydroxylamine gives 3,5-disubstituted isoxazoles regioselectively.

Crystallography, X-Ray↗