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 in 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 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 P Y 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 P Y relative activity of the four major metabolites varies xs While some bleeding caused by prasugrel is due to the on target effect of P Y it has recently been demonstrated in a P Y 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 andquot instantaneousandquot to hours Within this grant application we will assess whether the off target effects of prasugrel as defined by increased bleeding in the P Y knockout mice resides in the less potent P Y 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 PUBLIC HEALTH RELEVANCE Sickle cell disease SCD occurs in millions of people worldwide including about one out of every African American births There are currently no approved therapies for pediatric SCD Prasugrel the active ingredient in Effient r a drug approved for the treatment of acute coronary syndrome has recently demonstrated positive results in both adult and pediatric SCD patients Prasugrel is a mixture of two mirror image compounds enantiomers that spontaneously interconvert in the human body We have stabilized the enantiomers of prasugrel and plan to characterize the beneficial and detrimental effects of each enantiomer for the treatment of pediatric SCD including the potential to reduce or eliminate the serious side effect associated with Effient r the risk of bleeding