SBIR-STTR Award

This project has the long-term goal of developing melanocortin receptor (MCR) antagonists as therapeutic drugs for cachexia. Cachexia, characterized by a lack of appetite and a loss of lean body mass, is a frequent complication of malignancy, infectious diseases, and chronic inflammatory states. The melanocortin system appears to play a crucial role in the regulation of food intake and energy homeostasis. There is clear experimental evidence supporting the utility of MCR antagonists in the treatment of cachexia produced by malignancies, infectious diseases, and radiation. However, there is also experimental and clinical evidence that MCR ligands have unacceptable cardiovascular effects. However, we have data that most, if not all, of the cardiovascular effects of MCR ligands are not due to interactions with known MCRs. Using structure-activity-analysis of MCR ligands with in vivo assays, we demonstrate the dissociation of melanocortin from cardiovascular activity. Our "concept" is that appropriate derivatives of MC ligands can suppress cardiovascular side- effects, while leaving desired therapeutic actions intact. The Specific Aims and Milestones of our Phase I project are; 1. Design derivatives of MCR antagonists that suppress acute and chronic cardiovascular side- effects. Successful derivatives achieve Milestone #1. 2. Demonstrate that MCR antagonist derivatives with suppressed cardiovascular side-effects maintain anti-cachectic activity. Successful derivatives achieve Milestone #2. Achieving our Phase 1 milestones will demonstrate that we can increase the therapeutic index of MCR ligands, providing "proof of concept." Phase II of the project will involve the design and synthesis of centrally acting MCR antagonists to alleviate the metabolic sequelae of cachexia-inducing diseases.

Public Health Relevance:
Melanocortins (MCs) are naturally substances that have potential use as therapeutic agents in cachexia, a condition of reduced appetite with enhanced metabolic rate. However, MCs have unacceptable cardiovascular effects. We propose to develop MC drugs with reduced side-effects.

Thesaurus Terms:
17-Hydroxy-6-Methylpregna-4,6-Diene-3,20-Dione Acetate; 17.Alpha.-Acetoxy-6-Methylpregna-4,6-Diene-3,20-Dione; 6-Methyl-6-Dehydro-17.Alpha.-Acetoxyprogesterone; 6-Methyl-Delta-4,6-Pregnadien-17 Alpha-Ol-3,20-Dione Acetate; Achievement; Achievement Attainment; Acute; Adipose Tissue; Adverse Effects; Affect; Agonist; Amides; Amino Acid Sequence; Amino Acids; Anorexia; Appetite; Appetite Regulation; Arg-Phe-Nh2; Assay; Atrophic Arthritis; Autoregulation; Bioassay; Biologic Assays; Biological Assay; Body Weight Decreased; C-Terminal; Cachexia; Cancer Radiotherapy; Cancers; Cardiovascular; Cardiovascular Body System; Cardiovascular System; Cardiovascular System (All Sites); Central Nervous System; Chemical Structure; Chronic; Clinical; Communicable Diseases; Complication; Data; Desire For Food; Digestion; Disease; Disorder; Dissociation; Dose; Drug Therapy; Drugs; Eating; Energy Expenditure; Energy Metabolism; Family; Fatal Outcome; Fats; Fatty Tissue; Fatty Acid Glycerol Esters; Food Intake; Food Intake Regulation; Genome; Goals; Homeostasis; Hydrogen Oxide; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases And Manifestations; Infectious Disorder; Inflammatory; Inflammatory Arthritis; Intermediary Metabolism; Left; Ligands; Metbl; Maintenance; Maintenances; Malignant Neoplasms; Malignant Tumor; Medication; Megestrol Acetate; Metabolic; Metabolic Processes; Metabolism; Nervous System, Cns; Neuraxis; Obesity; Organ System, Cardiovascular; Outcome; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phe-Arg; Phe-Trp; Phenotype; Physiological Homeostasis; Play; Protein Structure, Primary; Rfamide; Rfamide Peptide; Radiation; Radiation Therapy; Radiotherapeutics; Radiotherapy; Receptor Protein; Regulation; Rheumatoid Arthritis; Role; Series; Structure; Syndrome; System; System, Loinc Axis 4; Therapeutic; Therapeutic Agents; Therapeutic Index; Treatment Side Effects; Trp-Tyr; Vascular, Heart; Viral Diseases; Virus Diseases; Water; Weight Loss; Weight Reduction; Adipose; Adiposity; Aminoacid; Arginylphenylalaninamide; Body Weight Loss; Circulatory System; Corpulence; Corpulency; Corpulentia; Cytokine; Design; Designing; Disease/Disorder; Drug Candidate; Drug/Agent; Effective Therapy; Experiment; Experimental Research; Experimental Study; Improved; In Vivo; Indexing; Irradiation; Malignancy; Meetings; Melanocortin Receptor; Mimetics; Neoplasm/Cancer; Obese; Obese People; Obese Person; Obese Population; Pharmacophore; Phenylalanylarginine; Phenylalanyltryptophan; Preclinical Study; Protein Sequence; Public Health Relevance; Ray (Radiation); Receptor; Research Study; Side Effect; Small Molecule; Social Role; Therapy Adverse Effect; Treatment Adverse Effect; Tryptophyl-Tyrosine; Tryptophyltyrosine; Viral Infection; Virus Infection; White Adipose Tissue; Wt-Loss; Yellow Adipose Tissue

Cachexia-anorexia syndrome is a life-threatening aspect to many diseases, in particular many forms of cancer or therapies for cancer. The obvious symptoms of this disease include lack of appetite, and a loss of lean body mass disproportionate to the reduction in caloric intake. However, the less obvious effects include multi-organ failure, due to high metabolic rate-induced apoptosis. The economic costs of cachexia are huge. The National Cancer Institute estimates that up to 40% of cancer deaths are directly due to cachexia, and it is likely a factor in a significant percent of other cancer fataliies. Hyperactivity of the central melanocortin (MC) system appears to be a common factor in most, if not all, forms of cachexia. In addition, recent evidence indicates that the lethargy (lack of activity/movement) associated with cachexia inducing diseases is not MC system mediated, but rather due to suppression to the central orexin system. Thus, the ideal anti-cachectic drug would combine the properties of a MC antagonist and orexin system agonist or stimulator. Analysis of MCR ligands with in vivo assays, demonstrated the dissociation of MC from cardiovascular (C-V) activity, suggesting a solution to the long-standing problem of MC C-V side-effects Our Phase 1 ""Proof of Concept"" was to produce derivatives of MC peptide antagonists that chronically suppressed C-V activity, while maintaining anti-anorexic activity. Phase 1 of this project was highly successful. We first made a detailed investigation of MC C-V actions, using arterial pressure, heart rate, and the electrocardiogram. MC ligand C-V activities replicate actions associated with RFamide peptides in different experimental models. The direct cardiac effects modeled the clinical symptoms of ""sick sinus syndrome"" and ""sudden cardiac arrest."" Thus, the endogenous RFamide system may have an etiological role in these human cardiac disorders. We then designed and synthesized MC cyclic peptide antagonists with an enzymatically stable C-terminal extension. This compound had no C-V activity, lacked the dose-limiting behavioral side-effects associated with other anti-cachectic MC antagonists, produced a 100% reversal of cachexia in an aggressive experimental cancer model, and suppressed cachexia-induced lethargy. Our Phase 2 Specific Aims are 1) design a MC antagonist peptide to maximize oral absorption and blood brain barrier transport;2) determine therapeutic index and pharmacokinetics in experimental models, and 3) confirm the anti-cachexia-anorexia effects in canine malignancies. Tensive Controls will complete the work necessary to develop anti-cachexia therapeutic, and move it into formal pre-clinical development. This will produce an anti-cachexia drug that will increase the treatment window for malignancies.

Public Health Relevance:
Melanocortins (MCs) are naturally substances that have potential use as therapeutic agents in cachexia, a condition of reduced appetite with enhanced metabolic rate. However, MCs have unacceptable cardiovascular effects. We propose to develop MC drugs with reduced side-effects.