Friday, April 19, 2024
4/19/2024
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 reduce reward from stimulants, thus aiding treatment of stimulant use disorders. We have developed pentilludin (NHB1109), a novel PTPRD phosphatase inhibitor, to advance to clinical use based on work with > 70 novel analogs. Pentilludin inhibits PTPRD phosphatase with Ki 700 nM potency. It is covered by a nonprovisional patent application filed with USPO. Pretreatments with 20 mg/kg pentilludin reduce rat amphetamine self administration and reduce mouse cocaine-conditioned place preferenc. Pentilludin displays good selectivity vs sites of 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. Repeated administration of doses > 150 mg/kg po to mice reduce oral intake and provide weight loss. 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). This supplement to UG3 support will move pentilludin closer to the threshold of first use in humans. It will allow us to add additional doses to our GLP studies in dogs and rats, heeding the advice of consultants that FDA will wish to see toxicities (reduced oral intake) in GLP as well as non GLP studies. We will continue to work with NIDA staff, experienced consultants and preIND meetings with FDA officials to complete an efficient series of IND-enabling research laboratory and GLP studies. Our GLP studies that will confirm nonGLP results re pentilludin biodistribution, pharmacodynamics and half-life/metabolism at NOAEL and toxic dose levels in rats and dogs in GLP studies. These data, as well as validation of final step GMP pentilludin syntheses that optimize purity and yield (with FDA approval) will provide a strong basis for an IND for pentilludin use in human phase I studies. These supplemental funds will thus aid our ability to reach milestones for the end of the UG3 support period: holding a preIND meeting with FDA staff and addressing each of the FDA concerns that result from this meeting, facilitating IND submission and phase I clinical studies of this promising compound.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
