title: Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals.
abstract: 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.
authors.affiliation: Mercachem, PO Box 6747, 6503 GE Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Veerman
authors.affiliation: Mercachem, PO Box 6747, 6503 GE Nijmegen, The Netherlands.
authors.forename: Toine
authors.initials: T
authors.lastname: van den Bergh
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Orrling
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Chimed
authors.initials: C
authors.lastname: Jansen
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Groenenborgerlaan 171, 2020 Wilrijk, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Groenenborgerlaan 171, 2020 Wilrijk, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: DNDi (Drugs for Neglected Diseases initiative), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.affiliation: DNDi (Drugs for Neglected Diseases initiative), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Ioset
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ewald E
authors.initials: EE
authors.lastname: Edink
authors.affiliation: Takeda, Takeda Pharmaceuticals International GmbH, Thurgauerstrasse 130, 8152 Glattpark-Opfikon, Zurich, Switzerland.
authors.forename: Hermann
authors.initials: H
authors.lastname: Tenor
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seebeck
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Iwan
authors.initials: I
authors.lastname: de Esch
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.affiliation: Mercachem, PO Box 6747, 6503 GE Nijmegen, The Netherlands; Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. Electronic address: g.j.sterk@vu.nl.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Sterk
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: C000611990:NPD-001; D010726:Phosphodiesterase Inhibitors; D015800:Protozoan Proteins; D011724:Pyridazines; D013777:Tetrazoles; D014344:Trypanocidal Agents; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C581006:PDEB1 protein, Trypanosoma brucei
keywords: African trypanosomiasis; Human PDEs; Phosphodiesterase; Pyridazinone; TbrPDEB1; Trypanosome brucei