Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones

Mey, Margaretha Van Der; Boss, Hildegard; Hatzelmann, Armin; Laan, Ivonne J. Van Der; Sterk, Geert Jan; Timmerman, H.

doi:10.1021/jm0110340

Cited by 20 publications

(25 citation statements)

References 18 publications

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“…The synthesis schemes 1 and 2 depict the synthetic routes of all compounds, some of which (1, 4, 5, 9, 11 and 14-18) have been published before as PDE4 inhibitors. 18,22 , while the others (6,7,8,10,12,13,(19)(20)(21)(22)(23)(24)(25) are new. For the compounds with the 3,4-dimethoxy (4, 5, 8-11) and the 4methoxy (6) substitution the synthesis route (Scheme 1) started with a Friedel-Craft acylation.…”

Section: Synthesismentioning

confidence: 99%

“…Subsequent condensation with hydrazine gave the pyridazinones which could be alkylated using sodium hydride in DMF. In all other cases (1,7,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) the route started with a Grignard reaction (Scheme 2) to obtain the gamma-ketopropionic acids. These carboxylic acids were then converted to the corresponding pyridazinones using the same chemistry as already outlined in scheme 1.…”

Section: Synthesismentioning

confidence: 99%

“…The synthesis of the compounds 1, 4, 5, 9, 11 and 14-18 has been described before. 18,22,29,30 and the remaining compounds (6, 7, 8, 10, 12, 13, 19-25) are prepared in an analogous manner and shortly described below.…”

Section: Molecular Dockingmentioning

confidence: 99%

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Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals

Veerman

Bergh

Orrling

et al. 2016

Bioorganic & Medicinal Chemistry

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Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4nM) and TbrPDEB2 (IC50: 3nM) (J. Infect. Dis.2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease.

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Section: Synthesismentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

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Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals

Veerman

Bergh

Orrling

et al. 2016

Bioorganic & Medicinal Chemistry

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“…Hexahydrophthalazinones family appears as a potent family of PDE4 inhibitors. 89 The structure-activity relationship studies showed that compounds bearing a cycloalkyl group at the position 2 exhibit the highest PDE4 inhibitory activities [p(IC 50 ) ¼ 8. 6-9.4].…”

Section: Miscellaneousmentioning

confidence: 99%

Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors

Castro

Jerez

Gil

et al. 2004

Medicinal Research Reviews

105

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The activity of phosphodiesterases (PDEs) is associated with a wide variety of diseases and an intense effort toward the development of specific PDEs inhibitors has been generated for the last years. They are the enzymes responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate, and their complexity, as well as their different functional role, makes these enzymes a very attractive therapeutic target. This review is focused on the role of PDEs played on immunomodulatory processes and the advance on the development of specific inhibitors, covering PDEs mainly related to the regulation of autoimmune processes, PDE4 and PDE7. The review also highlights the novel structural classes of PDE4 and PDE7 inhibitors, and the therapeutic potential that combined PDE4/PDE7 inhibitors offer as immunomodulatory agents. © 2004 Wiley Periodicals, Inc. Med Res Rev

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“…Several triazolophthalazines were found to exhibit antifungal and antibacterial activities 1–3. In addition, phthalazines and triazolophthalazines were found to exhibit anti‐inflammatory profiles 4–7. Among the already marketed COX‐2 inhibitors that comprise pyrazole nucleus, celecoxib (4‐[5‐(4‐tolyl)‐3‐(trifluoromethyl)‐1 H ‐pyrazol‐1‐yl]benzenesulfonamide), occupies a unique position as a potent and GI‐safe anti‐inflammatory and analgesic agent.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Some Triazolophthalazine Derivatives for Their Anti‐Inflammatory and Antimicrobial Activities

Habib

Farghaly

Ashour

et al. 2011

Archiv der Pharmazie

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Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.

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Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones

Cited by 20 publications

References 18 publications

Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals

Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals

Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors

Synthesis of Some Triazolophthalazine Derivatives for Their Anti‐Inflammatory and Antimicrobial Activities

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