Tobacco use is now recognized as the single most responsible cause of avoidable death worldwide representing approximately 10% of all deaths globally. Directly or indirectly, long term tobacco use has been implicated in complex major health disorders such as cancer, stroke, cardiovascular diseases, and mental disorders. In the USA alone, 30% of all cancer deaths and 87% of all lung cancer deaths are reported to be tobacco-use related. Besides the toll on human health, the estimated annual economic burden of tobacco use had reached over $193 billion both in lost productivity and associated health care costs in the USA. Although significant progress has been made towards the understanding and treatment of nicotine dependence, still approximately 21% of the adult population in the United States continues to smoke, and the increase in disease prevalence and health care expenditure has been positively correlated with smoking. In spite of the sustained national effort that has been undertaken to educate, encourage and help tobacco users to quit and abstain from smoking, only a small percentage of smokers manage to relinquish permanently without an interventional agent. The majority of current therapies for smoking cessation such as nicotine replacement therapy, bupropion and varenicline target the positive reinforcement or the pleasurable effects of nicotine. In contrast, there is currently no therapeutic available for the treatment of nicotine addiction that targets the brain stress systems or the negatively reinforced properties of nicotine addiction. In addition, the efficacy of most of these available therapeutic modalities has not been greatly satisfactory, and is further confounded by serious unwanted side effects such as insomnia, dry mouth, seizure, nausea, headache, psychotropic and gastrointestinal upset. Thus it becomes clear that current smoking cessation therapies are inadequate and that there is a significant need to develop therapeutic agents with new mechanisms of action for more effective treatment of tobacco addiction. An abundance of pharmacological and molecular biology data have implicated the significant roles that Orexin-1 (OX-R1) and Corticotropin-releasing factor receptor-1 (CRF-R1) play in the neurobiology of tobacco addiction and relapse. These data also support the convergent and complementary nature of these receptor signaling pathways. It is then logical to envision a therapeutic approach based on a single agent with a dual CRF-R1 and OX-R1 antagonist profile for nicotine addiction. To date, there is no small molecule with a dual antagonist activity on OX-R1 and CRF-R1. Hence, identifying a drug-like dual OX-R1:CRF-R1 antagonist would have great potential for the treatment of tobacco addiction and would represent a significant advancement in the field. Therefore, the specific aim of this Phase 1 STTR proposal is to identify, characterize, and develop a novel, potent (IC50 <1 uM on both OX- R1:CRF-R1) and selective (>10 x fold over OX-R2 and CRF2) antagonist chemical series, from which we will select a candidate with the best overall biological and physical-chemical properties for a Phase 2 STTR in-vivo study for potential use in the treatment of tobacco addiction and relapse. A successful identification of novel and dual OX-R1:CRF-R1 inhibitors with balanced in-vitro profile in this Phase 1 project would allow us to progress to a final lead optimization campaign focused on identifying pre- clinical leads with well-balanced in vivo pharmacokinetics (PK) parameters for key behavioral as well as pharmacological POC studies in rodent addiction and relapse models during a Phase 2 continuing grant.
Public Health Relevance: Directly or indirectly, long term tobacco use has been implicated in causing complex major health disorders such as cancer, stroke, cardiovascular diseases, and mental disorders that result in otherwise avoidable death worldwide. In the USA alone, 30% of all cancer deaths and 87% of all lung cancer deaths are reported to be related to tobacco use. The economic burden of tobacco use due to associated health-care costs and lost productivity has risen to over $193 billion annually in the US alone. Despite interest in quitting smoking, only a small percentage of smokers manage to relinquish permanently without an interventional agent. Unfortunately, the efficacy of most of the available smoking cessation therapeutic modalities has not been satisfactory, and is further confounded by serious unwanted side effects. It is the aim of this project to discover &develop novel therapeutic agents with unique mechanisms of action for more effective treatment of tobacco addiction and relapse.
Thesaurus Terms: 2-(Acetyloxy)-N,N,N-Trimethylethanaminium;21+ Years Old;3,4-Dihydroxyphenethylamine;4-(2-Aminoethyl)-1,2-Benzenediol;Acth-Releasing Factor;Aod Use;Acetylcholine;Address;Adult;Adult Human;Adverse Effects;Agreement;Alcohol Or Other Drugs Use;Amfebutamone;Animal Model;Animal Models And Related Studies;Anxiety;Apoplexy;Area;Asialia;Assay;Behavioral;Bioassay;Biologic Assays;Biological;Biological Assay;Biological Testing;Biotechnology;Brain;Brain Nervous System;Brain Vascular Accident;Bupropion;Crf Receptor Type 1;Crf-41;Crf-R1;Crf1 Receptor;Crh-1;Cancers;Cardiovascular Diseases;Cells;Cephalalgia;Cephalgia;Cephalodynia;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Cessation Of Life;Chemicals;Collaborations;Complex;Consumption;Corticoliberin;Corticotropin-Releasing Factor;Corticotropin-Releasing Factor-41;Corticotropin-Releasing Hormone;Corticotropin-Releasing Hormone-41;Cranial Pain;Crh1 Receptor;Dna Molecular Biology;Data;Death;Disease;Disorder;Dopamine;Drug Formulations;Drug Kinetics;Drugs;Economic Burden;Encephalon;Equilibrium;Ethanaminium, 2-(Acetyloxy)-N,N,N-Trimethyl-;Formulation;Freedom;Goals;Grant;Hcrt Protein;Hcrt/Orx;Hcrts/Orxs;Head Pain;Headache;Health;Health Care Costs;Health Costs;Health Expenditures;Healthcare Costs;Human;Hydroxytyramine;Hyposalivation;Ic50;In Vitro;Inhibitory Concentration 50;Insomnia;Insomnia Disorder;Intellectual Property;Loinc Axis 2 Property;Loinc Axis 4 System;Label;Lead;Letters;Liberty;Ligands;Link;Literature;Malignant Neoplasms;Malignant Tumor;Malignant Tumor Of The Lung;Malignant Neoplasm Of Lung;Man (Taxonomy);Medication;Medicinal Chemistry;Mental Disorders;Mental Health Disorders;Modality;Modeling;Modern Man;Molecular Biology;Moods;Mouth Dryness;Nature;Nausea;Neurobiology;Nicotine;Nicotine Dependence;Nicotine Replacement Therapy;Oxi Receptor (Ox1r);Opiate Peptides;Opioid Peptide;Pb Element;Pharmaceutic Chemistry;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmaceuticals;Pharmacokinetics;Pharmacologic Substance;Pharmacological Substance;Phase;Play;Population;Positive Reinforcements;Prevalence;Productivity;Property;Psychiatric Disease;Psychiatric Disorder;Pulmonary Cancer;Pulmonary Malignant Neoplasm;Pyridine, 3-(1-Methyl-2-Pyrrolidinyl)-, (S)-;Receptor Protein;Receptor Signaling;Relapse;Reporting;Rewards;Rodent;Rodentia;Rodents Mammals;Role;Route;Sttr;Screening Procedure;Seizures;Series;Signal Pathway;Sleeplessness;Small Business Technology Transfer Research;Smoke;Smoker;Smoking;Smoking History;Staging;Stress;Structure-Activity Relationship;System;Testing;Therapeutic;Therapeutic Agents;Tobacco;Tobacco Consumption;Tobacco Dependence;Tobacco Use;Treatment Side Effects;United States;Work;Xerostomia;Addiction;Addictive Disorder;Adult Human (21+);Adulthood;Analog;Aptyalism;Balance;Balance Function;Base;Brain Attack;Buproprion;Cardiovascular Disorder;Cease Smoking;Cerebral Vascular Accident;Cerebrovascular Accident;Chemical Property;Chemical Structure Function;Corticotropin Releasing Hormone;Corticotropin-Releasing Factor Receptor 1;Design;Designing;Develop Therapy;Disease/Disorder;Drug Discovery;Drug Market;Drug/Agent;Dry Mouth;Effective Therapy;Effective Treatment;Experience;Experiment;Experimental Research;Experimental Study;Gastrointestinal;Head Ache;Health Care Expenditure;Heavy Metal Pb;Heavy Metal Lead;Hypocretin;Hypocretin/Orexin;Hypocretins/Orexins;In Vivo;Inhibitor;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Interest;Intervention Development;Knowledge Base;Knowledgebase;Lung Cancer;Malignancy;Mental Illness;Model Organism;Negative Emotional State;Neoplasm/Cancer;Neurobiological;Neurochemical;Neurochemistry;New Therapeutics;Next Generation Therapeutics;Nicotine Addiction;Nicotine Replacement;Novel;Novel Therapeutics;Orexin;Orexin 1 Receptor;Pharmacophore;Pre-Clinical;Preclinical;Psychological Disorder;Quit Smoking;Receptor;Research Study;Response;Scaffold;Scaffolding;Screening;Screenings;Side Effect;Small Molecule;Smoking Cessation;Social Role;Stable Cell Line;Stop Smoking;Stroke;Structure Function Relationship;Substance Use;Success;Therapy Adverse Effect;Therapy Development;Tobacco Addiction;Treatment Adverse Effect;Treatment Development;Using Substances;Varenicline
