A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease.
McArthur JG, Svenstrup N, Chen C, Fricot A, Carvalho C, Nguyen J, Nguyen P, Prachikova A, Abdulla F, Vercellotti GM, Hermine O, Edwards D, Ribeil JA, Belcher JD, Maciel TT.
2019 Nov 20
The most common treatment for patients with sickle cell disease is the chemotherapeutic, hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin 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 sickle cell disease. IMR-687 increased cGMP and fetal hemoglobin in erythroid K562 and UT-7 cells and increased the percentage of fetal hemoglobin positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse sickle cell disease model, increased fetal hemoglobin 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 seen with physiologic 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 sickle cell disease.