Pharmacologically active pyridazine derivatives. Part 1.
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Animals↗
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Pyridazine derivatives XIV. Study of the vasorelaxant action of 6-aryl-5-piperidino-3-hydrazinopyridazines in isolated rat thoracic aorta: comparison with hydralazine.
1. For several years we have been working on the synthesis of modified hydrazinopyridazines which have proved to possess remarkable vasorelaxant and antihypertensive activity. We now report the vasodilator effects of three novel 6-aryl-5-piperidino-3-hydrazinopyridazines (1a, 1b and 1c), structurally related to the well-known antihypertensive drug hydralazine. 2. Hydralazine and the new hydrazinopyridazines relaxed, in a concentration-dependent and nonspecific way, the contractions elicited by noradrenaline or a high K+ concentration in rat aortic rings with or without endothelium. According to the IC50 (50% inhibitory concentrations) values obtained, the vasorelaxant potency of the new compounds was greater than that of hydralazine. 3. In a Ca2+-free medium, the contractions provoked by noradrenaline or caffeine were significantly inhibited by the new hydrazinopyridazines and by hydralazine. 4. Hydralazine and the novel molecules did not significantly modify basal, noradrenaline- or K+-induced 45Ca2+ uptake. 5. These results suggest that 1a, 1b and 1c have an endothelium-independent vasorelaxant activity greater than that of hydralazine in isolated rat aortic rings, which seems not to be mediated by a blockade of transmembrane Ca2+ movements through specific channels. This effect could be due, at least in part, to an intracellular mechanism of action.
Animals↗
Pyridazines. Part 28: 5-alkylidene-6-phenyl-3(2H)-pyridazinones, a new family of platelet aggregation inhibitors.
The synthesis and anti-platelet activity of several 5-alkylidene-6-phenyl-3(2H)-pyridazinones are described. The most active compounds are those that contain oxygenated functions (COOR, COMe) on the alkylidene fragment (6a, 6b and 6c).
Platelet Aggregation Inhibitors↗
5-aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
Glycogen Synthase Kinase 3↗
Pyridazines. Part XXIX: synthesis and platelet aggregation inhibition activity of 5-substituted-6-phenyl-3(2H)-pyridazinones. Novel aspects of their biological actions.
A series of 6-phenyl-3(2H)-pyridazinones with a diverse range of substituents in the 5-position have been prepared and evaluated in the search for new antiplatelet agents. A significant dependence of the substituent on the inhibitory effect has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at position 5 of the 6-phenyl-3(2H)-pyridazinone system influences both variations in the antiplatelet activity and the mechanism of action.
3',5'-Cyclic-AMP Phosphodiesterases↗
Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their corresponding 4,5-disubstituted-3-(2H)-pyridazinone analogues as new substrates for alpha1-adrenoceptor selective antagonists: synthesis, modeling, and binding studies.
A series of phenylpiperazinylalkyl moieties were attached to monocyclic or bicyclic substituted pyridazinones and the new compounds tested for their affinity towards alpha1-adrenoceptor and its alpha1a, alpha1b and alpha1d subtypes, as well as serotonin 5-HT1A receptor. Several analogues (5, 6, 9, and 10) showed remarkable potency and selectivity towards alpha1a, and alpha1d with respect to alpha1b subtype. None of the test compounds exhibited significant affinity for 5-HT1A receptor. Finally, on the basis of the alpha1-AR subtypes 3D models recently proposed, we have elaborated theoretical interaction models for the new compounds. The theoretical study allowed us to predict the affinity of the new compounds as well as to infer the structural/dynamics determinants of their interaction with the three alpha1-AR subtypes.
Adrenergic alpha-Antagonists↗
Synthesis and structure-affinity relationships at the central benzodiazepine receptor of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines.
A series of 2-aryl-3-chloro-2H-pyridazino[4,3-b]indoles, 2-aryl-3-methoxy-2H-pyridazino[4,3-b]indoles, and 2-aryl-2,5-dihydroindeno[1,2-c]pyridazino-3(3H)-ones has been prepared and tested for their ability to inhibit the [3H]flunitrazepam binding to the central benzodiazepine receptor. SAR are presented and discussed in comparison with existing pharmacophore models.
Hydrogen Bonding↗
Spectrofluorometric determination of tetrahydro-6-oxo-3-pyridazine carboxylic acid (PCA) with o-nitrobenzaldehyde.
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Aldehydes↗
Cardiotonic agents. 4. Synthesis and biological evaluation of N-substituted 2,4,4a,5-tetrahydro-3H-indeno[1,2-c]pyridazin-3-ones: rigid structures derived from CI-930 and analogues.
Several N-substituted 3H-indeno[1,2-c]pyridazinones (1-23) and a benzo[h]cinnolinone (24), which were designed as rigid structural modifications of 5-alkyl-4,5-dihydro-6-[4-N-substituted phenyl]-3(2H)-pyridazinones (ib-d), were synthesized and evaluated for positive inotropic activity. Most of these tricyclic pyridazinones (1-11, 14-15, 22-23) demonstrated potent positive inotropic activity comparable to the corresponding phenylpyridazinones related to I.
Animals↗
Nonsteroidal cardiotonics. 3. New 4,5-dihydro-6-(1H-indol-5-yl)pyridazin-3(2H)-ones and related compounds with positive inotropic activities.
A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.
Animals↗
Mesoionic pyridazine ribonucleosides. A novel biologically active nucleoside metabolite.
4-Cyano-3-oxido-1-beta-D-ribofuranosylpyridazinium (10a) has been prepared from 4-cyano-3(2H)-pyridazinone (4) by using a low-temperature, kinetically controlled, silyl Hilbert-Johnson reaction followed by deblocking of the resulting triacetate derivative, 8a, with NaHCO3 in methanol. 10a is apparently the first example of a mesoionic analogue of a pyrimidine nucleoside. It was discovered as a urine metabolite of 4-cyano-3(2H)-pyridazinone (4) in mice. 10a possesses Gram-negative antibacterial activity in vivo against a systemic Escherichia coli infection in mice with an ED50 of 25-50 mg/kg. A series of 4-substituted 3-oxidopyridazinium ribonucleosides, 11a-h, were synthesized as analogues of 10a. 4-Chloro-3-oxido-1-beta-D-ribofuranosylpyridazinium (11a) was found to be several times more active than 10a against E. coli in vitro although it showed no in vivo activity.
Animals↗
Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound.
Excessive glial activation, with overproduction of cytokines and oxidative stress products, is detrimental and a hallmark of neurodegenerative disease pathology. Suppression of glial activation is a potential therapeutic approach, and protein kinases are targets of some antiinflammatory drugs. To address an unmet need for selective inhibitors of glial activation, we developed a novel 3-amino-6-phenylpyridazine derivative that selectively blocks increased IL-1 beta, iNOS, and NO production by activated glia, without inhibition of potentially beneficial glial functions.
Animals↗
A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one.
We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED(90) values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).
Administration, Oral↗
A new pyridazine series of GABAA alpha5 ligands.
Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA alpha5 inverse agonists, made it an attractive molecule for further exploration. This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes.
Animals↗
Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.
Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.
Adenosine Triphosphate↗
7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.
There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
Animals↗
Pyridazines. LI. Synthetic approaches to pyridazino(2,3-a)-1,3,5-triazines, a novel heterocyclic system.
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Magnetic Resonance Spectroscopy↗
Hydrogen bond directed synthesis of pyridazine and naphthyridine containing macrocycles.
This work describes a high-yielding, one-step synthesis of pyrizadine and naphthyridine containing macrocycles directed by intramolecular H-bonding.
Crystallography, X-Ray↗