Summary/abstract: Stimulants provide major challenges in the US. In a recent year, almost 7.5 million Americans reported cocaine or methamphetamine use. More than 32 million amphetamine prescriptions were written for conditions including attention deficit hyperactivity disorder and narcolepsy. 1.75 million Americans reported amphetamine or cocaine use disorders. There were > 212,000 admissions to stimulant use disorder treatment programs. However, there is no FDA-approved stimulant use disorder pharmacotherapeutic. The receptor type protein tyrosine phosphatase D (PTPRD) is a novel target for new drugs that aid abstinence from stimulants by reducing reward from stimulants. We have developed pentilludin (NHB1109), a novel PTPRD phosphatase inhibitor, to advance to clinical use. Pentilludin inhibits PTPRD phosphatase with Ki 690 nM potency. Its composition of matter patent application has received notice of allowance from USPO. Pretreatments with 20 mg/kg pentilludin reduce rat amphetamine self-administration and mouse cocaine- conditioned place preference. Pentilludin displays good selectivity vs sites assessed by EUROFINS screens and phosphatases that include PTP1B. It provides good results in studies of its carcinogenicity, hERG channel effects, CYP activities and CYP induction. It is metabolized in plasma > hepatic microsomes and competes for activity of recombinant paraoxonases, supporting its role as a substrate for these plasma enzymes. There is no toxicity noted in dogs, rats or mice repeatedly dosed with 15, 75 and 100 mg/kg/d, respectively (chemistry, hematology or histopathology except idiosyncratic rodent renal tubular basophilic lesions not seen in dogs, a pattern found with many drugs that provide no human toxicity). Repeated mouse doses > 150 mg/kg/d po provide dose-limiting reductions in oral intake and weight. We have recently completed a successful FDA preIND meeting (PIND #169179). FDA indicated that our proposed studies were generally correct, but that we needed to add more dosing levels, greater n and to repeat some nonGLP work under GLP conditions. This supplement to UG3 support will allow us to complete more of the expanded list of GLP studies required by FDA, moving pentilludin closer to the threshold of first use in humans. It will allow us to add additional n and additional dose levels to our previously-planned rat and dog GLP studies. It will allow us to repeat genotoxicity and hERG work under GLP conditions. We will work with NIDA staff and experienced consultants to complete an efficient a series of these IND-enabling studies. We anticipate that this supplement will allow us to satisfy NIDA criteria for transition to UH3. UH3 work, in turn, will allow us to complete GMP pentilludin synthesis, IND submission, first in human/ascending dose studies and repeated dose phase I studies. This supplementary support will allow us to move closer to these goals for this highly-promising compound.