The present proposal seeks to prepare prodrug esters of a 2-phenylmorpholinol (BW1555U88) inhibitor of the dopamine and norepinephrine transporters for the treatment of ADHD. 1555U88 (aka GW320659A) has been in >1000 patients and, in phase II human trials, was effective for treating ADHD. However, direct-acting inhibitors of the DAT have intrinsic abuse liability, related in part to euphoria resulting from rapid inhibition of the DAT. It is reasoned that prodrug esters of 1555U88 will not directly inhibit the dopamine transporter but, following hydrolysis by intestinal carboxylesterase, will yield the active drug. The proposal seeks funding for the synthesis and evaluation of amino acid esters of 1555U88. Building on the example of Valtrex(r) (valcyclovir), intestinal peptide transporters, may facilitate the oral absorption of amino acid esters (e.g. valine) of either the aminoketone precursor of 1555U88 or of 1555U88 itself. Esters of valine, alanine and methionine are suggested by example of valcyclovir, where esters of these amino acid esters were transported with higher efficiency than esters of other amino acids. The proposal, in phase I, will demonstrate: 1. whether such a molecule will have low intrinsic affinity for the DAT; 2. whether such molecules can be hydrolyzed by human liver to yield 1555U88, and; 3. if the ester conjugates can be taken up into caco-2 cells (by hPEPT1 and 2). If successful, Phase II money will complete the preclinical studies required for support of human clinical trials.
