NPD-001
目录号 : GC64844NPD-001 是一种有效的布氏锥虫磷酸二酯酶 TbrPDEB1 和 TbrPDEB2 抑制剂,其 IC50 值分别为 4 nM 和 3 nM。NPD-001 也抑制人类磷酸二酯酶 PDEs。NPD-001 表现出良好的抗锥虫体活性,IC50 为 80 nM。
Cas No.:469863-16-9
Sample solution is provided at 25 µL, 10mM.
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NPD-001 is a potent Trypanosoma brucei phosphodiesterases TbrPDEB1 and TbrPDEB2 inhibitor, with IC50 values of 4 and 3 nM, respectively. NPD-001 also inhibits human PDEs (phosphodiesterases). NPD-001 shows good anti trypanosomal activity, with an IC50 of 80 nM[1].
[1]. Veerman J, et al. Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals. Bioorg Med Chem. 2016 Apr 1;24(7):1573-81.
Cas No. | 469863-16-9 | SDF | Download SDF |
分子式 | C33H40N6O4 | 分子量 | 584.71 |
溶解度 | DMSO : 100 mg/mL (171.02 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.7102 mL | 8.5512 mL | 17.1025 mL |
5 mM | 0.342 mL | 1.7102 mL | 3.4205 mL |
10 mM | 0.171 mL | 0.8551 mL | 1.7102 mL |
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Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals
Bioorg Med Chem 2016 Apr 1;24(7):1573-81.PMID:26935942DOI:10.1016/j.bmc.2016.02.032.
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.
Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi
J Antimicrob Chemother 2020 Apr 1;75(4):958-967.PMID:31860098DOI:10.1093/jac/dkz516.
Background: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity. Objectives: As phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T. cruzi strains and parasite forms relevant for human infection. Methods: In vitro trypanocidal activity of the inhibitors was assessed alone and in combination with benznidazole. Their effects on parasite ultrastructural and cAMP levels were determined. PDE mRNA levels from the different T. cruzi forms were measured by quantitative reverse transcription PCR. Results: Five TcrPDEs were found to be expressed in all parasite stages. Four compounds displayed strong effects against intracellular amastigotes. Against bloodstream trypomastigotes (BTs), three were at least as potent as benznidazole. In vitro combination therapy with one of the most active inhibitors on both parasite forms (NPD-040) plus benznidazole demonstrated a quite synergistic profile (xΣ FICI = 0.58) against intracellular amastigotes but no interaction (xΣ FICI = 1.27) when BTs were assayed. BTs treated with NPD-040 presented disrupted Golgi apparatus, a swollen flagellar pocket and signs of autophagy. cAMP measurements of untreated parasites showed that amastigotes have higher ability to efflux this second messenger than BTs. NPD-001 and NPD-040 increase the intracellular cAMP content in both BTs and amastigotes, which is also released into the extracellular milieu. Conclusions: The findings demonstrate the potential of PDE inhibitors as anti-T. cruzi drug candidates.