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PubMed1985

Enhanced prostacyclin biosynthesis and decreased thromboxane formation by 3-dimethylamino 5-(2',6'-dichlorobenzylidene) 6-methyl (4H)-pyridazine (PC 89).

The effects of 3-dimethylamino 5-(2',6'-dichlorobenzylidene) 6-methyl (4H)-pyridazine (PC 89) on the biosynthesis of PG I2 and TX A2 using horse aorta and horse platelet microsomes as sources of enzymes and arachidonic acid as substrate, were investigated. PC 89 (1.10(-6) M- 1.10(-3) M) dose-dependently - enhanced the biosynthesis of PG I2: the AD50 was 6.8 X 10(-6) M +/- 1.2 X 10(-9) M, the Vmax did not vary significantly with concentrations: PC 89 increased the affinity of enzyme for substrate - but inhibited TX A2 biosynthesis (ID50 = 3.31 X 10(-3) M +/- 4.8 X 10(-7) M): this inhibiting action was not of competitive type. Owing to this dual activity of preventing TX A2 formation and stimulating PG I2 biosynthesis, PC 89 could be a valuable drug for myocardial ischemia and atherosclerosis therapeutics.

Animals↗
PubMed2004

Synthesis and biological evaluation of 6-aryl-6H-pyrrolo[3,4-d]pyridazine derivatives as high-affinity ligands of the alpha(2)delta subunit of voltage-gated calcium channels.

A novel class of 2H-pyrrolo[3,4-c]pyridazine ligands of the alpha (2) delta subunit of voltage-gated calcium channels is described. Compound 4a with high affinity toward alpha (2) delta was identified through structure-activity relationship studies of the lead compound. Tritiated ligand [(3)H]-4b was synthesized to demonstrate that this ligand binds to the same site as Gabapentin toward alpha (2) delta subunit of voltage-gated calcium channels.

Calcium Channels↗
PubMed2004

Pyridazine derivatives and related compounds. Part 13: Synthesis and antimicrobial activity of some pyridazino[3',4':3,4]pyrazolo[5,1-c]-1,2,4-triazines.

A general method for the preparation of substituted pyridazinopyrazolotriazines is reported. 3-Aminopyrazolo[3,4-d]pyridazine was diazotized and coupled with active methylene reagents to afford the tricyclic pyridazino[3',4':3,4]pyrazolo[5,1-c]-1,2,4-triazines with substituents such as methyl, phenyl, ethoxycarbonyl, acetyl or benzoyl, depending on the methylene reagent used. In addition several condensation reactions with hydrazines gave the corresponding acid hydrazide and/or hydrazones. Reactions of 3 with aromatic aldehydes afforded hydrazones. The products were screened for their antimicrobial activity against five microorganisms.

Anti-Bacterial Agents↗
PubMed2004

Identification of 2,3-diaryl-pyrazolo[1,5-b]pyridazines as potent and selective cyclooxygenase-2 inhibitors.

GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.

Administration, Oral↗
PubMed2005

Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase.

Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-alpha production in mice and exhibited good efficacy in the rat collagen induced arthritis model.

Binding Sites↗
PubMed2005

Antibacterial and antifungal activities of new pyrazolo[3,4-d]pyridazin derivatives.

Several new pyrazolo[3,4-d]pyridazin derivatives were prepared by the reaction of two [corrected] 1H-pyrazole-3-carboxylic acids and various hydrazines. The compounds were tested for antimicrobial activities against Gram-negative, Gram-positive bacteria and fungi. The compounds named as 7e, f had the highest antimicrobial activities against Gram-negative, Gram-positive bacteria and fungi with minimum inhibitory concentrations in the range of 0.31 to<0.0024 mg ml(-1) .

Anti-Bacterial Agents↗
PubMed2006

E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, is a novel, selective and competitive dipeptidyl peptidase-IV inhibitor.

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, which is a novel imidazopyridazinone-derived DPP-IV inhibitor. E3024 inhibited recombinant human and mouse DPP-IV with IC50 values of approximately 100 nM. E3024 inhibited DPP-IV in human, mouse, rat and canine plasma with IC50 values of 140 to 400 nM. In contrast, E3024 did not inhibit DPP-8 or DPP-9 activity. Kinetic analysis indicated that E3024 is a competitive DPP-IV inhibitor. In Zucker fa/fa rats, E3024 (1 mg/kg) reduced glucose excursion after glucose load, with increases in plasma insulin and active glucagon-like peptide-1 levels. In fasted rats, this compound did not cause hypoglycemia. In a rat 4-week toxicological study, no notable changes were found at doses up to 750 mg/kg. The present preclinical studies indicate that E3024 is a novel selective DPP-IV inhibitor with anti-diabetic effects and a good safety profile.

Animals↗
PubMed2003

Synthesis and biological evaluation of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines as new ligands of central and peripheral benzodiazepine receptors.

A large number of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines were synthesised and tested to evaluate their binding affinities at both central (CBR) and peripheral (PBR) benzodiazepine receptors. Relatively good PBR binding affinities were found for ligands belonging to the 3-arylmethyloxy-pyridazinoindole series, whereas only 2-aryl-indenopyridazines 7a, 8a and 10a display a weak binding affinity for CBR. To find out the main structural determinants affecting PBR affinity, a molecular modelling study based on the comparative analysis of the three-dimensional properties of four properly selected derivatives 24a, 3b, 18a and 10d, with those of highly active and selective PBR ligands, taken as reference, was performed.

Animals↗
PubMed1998

Investigations on the synthesis and properties of N-phenyl derivatives of 1,4-dioxo(1,4,5-trioxo)-1,2,3,4-tetra(1,2,3,4,5,6-hexa) hydropyrido-[3,4-d]pyridazines and allied compounds.

2-(1-Piperidino)- and 2-(4-methyl-1-piperazinyl)-6-methyl-3,4-pyridinedicarboximides (1, 2) react with N-phenylhydrazine yielding N-phenylamino-3,4-pyridinedicarboximides (7, 8). The same reaction with 1,6-dimethyl-2-oxo-1,2-dihydro- and 2-chloro-6-methyl-3,4-pyridinedicarboximides (3, 17) gives the salts of the corresponding N-phenylpyridopyridazines with phenylhydrazine (13, 18), which transform into N-phenylaminoimides (14, 19) during boiling in 80% acetic acid. Compounds 7, 8 and 14 isomerize to the corresponding 2-phenyl-1,4-dioxo(1,4,5-trioxo)-1,2,3,4-tetra(1,2,3,4,5,6-hexa) hydropyrido[3,4-d]pyridazines (9, 10, 15) under the influence of heating in alcoholic solution of C2H5ONa or CH3ONa. Only in the case of imide 19 are 2- and 3-phenyl isomers (20 and 21) formed under these conditions. Some of the obtained compounds were pharmacologically active.

Animals↗
PubMed2001

Synthesis and bioactivities of novel 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one derivatives: inhibitors of interleukin-1 beta (IL-1beta) production.

New 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one derivatives were prepared, and their abilities to inhibit IL-1beta production were evaluated. Some compounds showed potent inhibitory activity against IL-1beta production in HL-60 cells stimulated with lipopolysaccharide (LPS). The synthesis and structure-activity relationships of these compounds are described.

Administration, Oral↗
PubMed2003

Rational approaches towards reversible inhibition of type B monoamine oxidase. Design and evaluation of a novel 5H-Indeno[1,2-c]pyridazin-5-one derivative.

The stereoelectronic properties of several potent reversible monoamine oxidase B (MAO-B) inhibitors were studied with a view to develop a pharmacophore model for reversible MAO-B inhibition. This study suggested that important specific H-bond and hydrophobic interactions are required for potent and selective MAO-B inhibition. These requirements were applied in the design and synthesis of a novel reversible and selective MAO-B inhibitor, 3-methyl-8-(4,4,4-trifluoro-butoxy)indeno[1,2-c]pyridazin-5-one, that is ca. 7000 times more selective as an inhibitor for MAO-B than for MAO-A, with K(i(MAO-B)) in the low nanomolar range.

Drug Design↗
PubMed2002

Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B).

A series of novel pyridazine analogues were prepared and the structure-activity relationship of their behavior as inhibitors of PTP1B was evaluated. Most of the analogues had potencies in the low micromolar range. The in vitro kinetics of this compound series demonstrated that they were reversible non-competitive binders. This indicates that there may exist another site in the enzyme through which enzyme activity can be inhibited, which is not a recognized interaction domain. Some of the analogues exhibited high selectivity for other PTPases, for example, compound 12 mp showed 20-fold selectivity for PTP1B (IC50=5.6 microM) versus both TCPTP and LAR (>100 microM, respectively). In contrast to many tyrosine phosphatase mimetic inhibitors, this compound class lacks negative charge and thus showed high permeability across cell membranes. Selective analogues in the series were analyzed in an in vitro cellular assay, which showed increased insulin-stimulated insulin receptor phosphorylation.

Animals↗
PubMed1995

Inhibition of monoamine oxidase-B by 5H-indeno[1,2-c]pyridazines: biological activities, quantitative structure-activity relationships (QSARs) and 3D-QSARs.

A large series (66 compounds) of indeno[1,2-c]pyridazin-5-ones (IPs) were synthesized and tested on their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. All of the tested compounds acted preferentially on MAO-B displaying weak (nonmeasurable IC50 values) to high (submicromolar IC50 values) activities. The most active compound was p-CF3-3-phenyl-IP (IC50 = 90 nM). Multiple linear regression analysis of the substituted 3-phenyl-IPs yielded good statistical results (q2 = 0.74; r2 = 0.86) and showed the importance of lipophilic, electronic, and steric properties of the substituents in determining inhibitory potency. Various comparative molecular field analysis studies were performed with different alignments and including the molecular lipophilicity potential. This led to a model including the steric, electrostatic and lipophilicity fields and having a good predictive value (q2 = 0.75; r2 = 0.93).

Computer Graphics↗
PubMed1981

Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines.

The synthesis of a series of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines (VIII) is reported. Some of these derivatives show activity in tests predictive of anxiolytic activity [(a) protection against pentylenetetrazole-induced convulsions; (b) thirsty rat conflict procedure]. They also represent a new class of compound which inhibits [3H]diazepam binding. Structure--activity correlations, as well as the ability of structures VIII to inhibit [3H]diazepam binding (in vitro), are discussed.

Animals↗