Stabilized Prasugrel enantiomers for pediatric sickle cell disease



 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a severe inherited disease that occurs in about 1 in 2,500 newborns in the U.S, greater than that of any other condition detected by newborn blood screening. Only one treatment, hydroxyurea, is approved for the complications of SCD in adult patients. Hydroxyurea is not approved in children due to concerns regarding possible genotoxicity and carcinogenesis. There are currently three ongoing clinical trials with drug candidates for pediatric SCD patients. The only treatment that has progressed to Phase 3 is prasugrel, the active ingredient in Effient(r) which is approved for acute coronary syndrome (ACS). The major concern of prasugrel for ACS and SCD patients is the black box warning for increased risk of bleeding. This is a significant concern in pediatric SCD pediatric patients who have increased risk of hemorrhagic stroke. The beneficial effects of prasugrel have been linked to the irreversible binding of its metabolites to P2Y12 receptors that leads to reduced aggregation of platelets. Prasugrel is a racemic mixture of two mirror image compounds (enantiomers) that spontaneously interconvert in vivo. As such, exposing patients to just one enantiomer and its corresponding metabolites is impossible. The P2Y12 relative activity of the four major metabolites varies 16-190xs. While some bleeding caused by prasugrel is due to the on-target effect of P2Y12, it has recently been demonstrated in a P2Y12 knockout mouse model that the increased bleeding risk is likely due largely to off-target effects. Our aim is to develop a stabilized, single enantiomer of prasugrel for the treatment of pediatric SCD with dramatically reduced risk of bleeding. We discovered a method to stabilize the individual enantiomers of rapidly interconverting racemic drugs by replacing the hydrogen at the chiral center with deuterium. By adding deuterium to prasugrel, we have slowed the racemization half-life from "instantaneous" to 2.2 hours. Within this grant application we will assess whether the off-target effects of prasugrel, as defined by increased bleeding in the P2Y12 knockout mice, resides in the less potent P2Y12 metabolites derived from a single enantiomer of prasugrel. We will also assess the on-target efficacy with platelets in an ex vivo platelet activation model to confirm that the two metabolites derived from the other enantiomer account for all or most of the desired platelet aggregation activity. These results will allow us advance a single enantiomer of deuterated prasugrel to preclinical development for pediatric SCD.