210467-65-5Relevant articles and documents
Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals
Veerman, Johan,Van Den Bergh, Toine,Orrling, Kristina M.,Jansen, Chimed,Cos, Paul,Maes, Louis,Chatelain, Eric,Ioset, Jean-Robert,Edink, Ewald E.,Tenor, Hermann,Seebeck, Thomas,De Esch, Iwan,Leurs, Rob,Sterk, Geert Jan
, p. 1573 - 1581 (2016/03/16)
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: 4 nM) and TbrPDEB2 (IC50: 3 nM) (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.
Design, synthesis and evaluation of dual pharmacology β2- adrenoceptor agonists and PDE4 inhibitors
Huang, Ling,Shan, Wenjun,Zhou, Qi,Xie, Jiaxing,Lai, Kefang,Li, Xingshu
supporting information, p. 249 - 253 (2014/01/17)
A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50 = 1.05 nM, pEC50 = 9.0) and potent PDE4B2 inhibitory activities (IC50 = 0.092 μM).
Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone: Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD
Liu, Anqiu,Huang, Ling,Wang, Zhiren,Luo, Zonghua,Mao, Fei,Shan, Wenjun,Xie, Jiaxing,Lai, Kefang,Li, Xingshu
, p. 1548 - 1552 (2013/03/28)
A novel class of dual pharmacology bronchodilators targeting both β2-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better β2-adrenoceptor agonist activities (pEC50 = 8.47-9.20) than the reference compound salmeterol (pEC50 = 8.3) and good inhibitory activity on PDE4B2 (IC 50 = 0.235-1.093 μM).
Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD
Shan, Wen-Jun,Huang, Ling,Zhou, Qi,Jiang, Huai-Lei,Luo, Zong-Hua,Lai, Ke-Fang,Li, Xing-Shu
supporting information; experimental part, p. 1523 - 1526 (2012/04/04)
We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both b2-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC50 = 0.278 μM, which was more potent than phthalazinone, IC50 = 0.520 lM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC50 = 9.3).
Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors
Kagayama, Kohei,Morimoto, Tatsuya,Nagata, Seigo,Katoh, Fumitaka,Zhang, Xin,Inoue, Naoki,Hashino, Asami,Kageyama, Kiyoto,Shikaura, Jiro,Niwa, Tomoko
experimental part, p. 6959 - 6970 (2009/12/24)
Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure-activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-α production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis.
PHTHALAZINONE-DERIVATIVES AS PDE4 INHIBITORS
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Page/Page column 30-31, (2008/06/13)
The compounds of a certain formula (1), in which R1, R2, R3, R9 and n have the meanings as given in the description, are novel effective PDE4 inhibitors.
Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution, absolute configuration, and PDE4 inhibitory activity of cis-tetra- and cis-hexahydrophthalazinones
Van der Mey, Margaretha,Boss, Hildegard,Couwenberg, Dennis,Hatzelmann, Armin,Sterk, Geert J.,Goubitz, Kees,Schenk, Henk,Timmerman, Hendrik
, p. 2526 - 2533 (2007/10/03)
Recently, we reported that 4-catechol-substituted cis-(±)-4a,5,6,7,8,8a-hexa- and cis-(±)- 4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only w
Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues
Van der Mey,Hatzelmann,Van der Laan,Sterk,Thibaut,Timmerman
, p. 2511 - 2522 (2007/10/03)
A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the cGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC50 = 6.5) as well as PDE3 (pIC50 = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC50 = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition.
Phthalazinones
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, (2008/06/13)
PCT No. PCT/EP98/00124 Sec. 371 Date Jul. 14, 1999 Sec. 102(e) Date Jul. 14, 1999 PCT Filed Jan. 12, 1998 PCT Pub. No. WO98/31674 PCT Pub. Date Jul. 23, 1998Compounds of formula I wherein R1, R2, R3, R4 and R5 have the means set forth in the description are selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4), which are effective bronchial therapeutics.
