@article{James G. McArthur_Niels Svenstrup_Chunsheng Chen_Aurelie Fricot_Caroline Carvalho_Julia Nguyen_Phong Nguyen_Anna Parachikova_Fuad Abdulla_Gregory M. Vercellotti_Olivier Hermine_Dave Edwards_Jean-Antoine Ribeil_John D. Belcher_Thiago T. Maciel_2020, place={Pavia, Italy}, title={A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease}, volume={105}, url={https://haematologica.org/article/view/9281}, DOI={10.3324/haematol.2018.213462}, abstractNote={The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated <em>in vitro</em> using a two-phase liquid culture of CD34<sup>+</sup&gt; progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.}, number={3}, journal={Haematologica}, author={James G. McArthur and Niels Svenstrup and Chunsheng Chen and Aurelie Fricot and Caroline Carvalho and Julia Nguyen and Phong Nguyen and Anna Parachikova and Fuad Abdulla and Gregory M. Vercellotti and Olivier Hermine and Dave Edwards and Jean-Antoine Ribeil and John D. Belcher and Thiago T. Maciel}, year={2020}, month={Mar.}, pages={623-631} }