Research Project
10022080
Abstract Alcoholism and alcohol-associated diseases represent a major health challenge worldwide, leading to over 88,000 annual deaths in the USA at an annual public-health cost of nearly 250 billion dollars. Current treatments include counseling and support groups coupled with medications that reduce the desire to drink (such as by altering opioid and glutamate pathways) or by use of treatments that cause unpleasant reactions while drinking (disulfiram). Unfortunately, these treatments provide variable and/or partial responses; so, new therapies are needed. Our longstanding interest in mechanisms driving sugar-associated liver disease have revealed that these mechanisms affect sugar craving as well. The big breakthrough was the novel discovery that these same mechanisms affect the preference for alcohol. The mechanism responsible for these effects involves an enzyme, fructokinase (also known as ketohexokinase (KHK)), which is the first enzyme in fructose metabolism (a component of sugar, or sucrose). The preference for alcohol can be substantially blocked in mice lacking KHK. Pursuant to this discovery, new first in class of drugs to combat alcoholism have been generated by Colorado Research Partners, LLC (CRP). An advantage to inhibition of KHK is that inhibition of this target is safe (humans lacking fructokinase live normally) and involves a non-vital pathway (fructose metabolism), which is in opposition to other interventions that interrupt neural signal pathways with pluripotent functions or have severe side effects. Several potent compounds (60?160 nM Ki values) have been developed, which are selective, active in vivo, orally bioavailable, and have reasonable pharmacokinetic (PK) profiles. We have assembled an expert team, have both composition-of-matter and methods-of-use intellectual property protection, and have a strong commercialization plan. Our first aim will optimize our lead compound by: 1) Fine tuning the potency and selectivity using computer modeling and crystallography to guide the structure/activity relationship (SAR); 2) Optimizing oral bioavailability, hepatic delivery and metabolism; 3) Assuring safety by running assays such as CYP450-inhibition profile, hERG binding, protein kinase-selectivity screen, Ames test, and in vivo safety-toxicity and tumorigenicity studies; and 4) Completion of preclinical studies focusing on in vivo efficacy for both prevention and treatment of alcohol addiction using murine and rat models. Our second aim will include 1) IND- enabling studies including final toxicity and PK profiles of our lead compound in two species (rat and dog) and 2) Two Phase I trials in healthy individuals consisting of a single dose, accelerating study, and a multiple dose, accelerating 7 day study of KHK inhibition in healthy humans. These latter studies will investigate both the PK profile in humans and safety of the drug. Completion of these studies will result in a safe and effective drug of a novel class positioned for Phase 2 trials to treat alcoholism and alcohol-use disorders.
