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

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 7; pp. 1573 - 1581
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2016; Elsevier
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; African trypanosomiasis; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Human PDEs; Humans; Life Sciences & Biomedicine; Molecular Structure; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Phosphodiesterase; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Physical Sciences; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - metabolism; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Pyridazinone; Science & Technology; Structure-Activity Relationship; TbrPDEB1; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology; Trypanosome brucei; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - parasitology; MOE; TbrPDEB2; TbrPDEB1; MW; Pyridazinone; Human PDEs; African trypanosomiasis; Phosphodiesterase; Trypanosome brucei; SELECTIVE PDE4 INHIBITORS; DESIGN; PHARMACOLOGICAL VALIDATION; CRYSTAL-STRUCTURE; SLEEPING SICKNESS; B1; BRUCEI PHOSPHODIESTERASES; CIS-HEXAHYDROPHTHALAZINONES; GENERATION; PARASITE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.02.032

[Display omitted] 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.