The broad goal of the SBIR proposal is to understand the pharmacology of phosphodiesterase 4 (PDE4) allosteric modulation in the CNS as it relates to psychiatric disorders. We recently described the discovery of isoform-selective, allosteric modulators of PDE4D that bind to a high affinity site on an N-terminal regulatory domain known as Upstream Conserved Region 2 (UCR2). The allosteric mechanism of action prevents the compounds from completely inhibiting cAMP hydrolysis, thereby reducing target-based toxicity. PDE4D modulators have greatly improved tolerability than earlier compounds such as rolipram. Rolipram previously was shown to have anti-depressant activity in human Phase II clinical trials but was poorly tolerated due to emesis. Three isoforms of PDE4 are expressed in brain (PDE4A, B &D). It previously has not been possible to develop isoform-selective PDE4 inhibitors, since earlier efforts have targeted the catalytic site, which is highly conserved among the PDE4 subtypes;thus, little is known regarding the pharmacology of PDE4 isoform selective compounds. Our immediate goal is to explore the possible clinical benefit of our investigational new drug, DG-071 in animal models of psychiatric disease, particularly depression. The proposed studies will determine the feasibility of developing DG-071 for the treatment of depression. The second specific aim of the SBIR proposal is to use structural guidance to design PDE4B selective allosteric modulators that distribute to brain. We will explore PDE4B CNS pharmacology, particularly in models of schizophrenia. The structural and medicinal chemistry studies will determine the feasibility in a Phase II SBIR of developing PDE4B selective allosteric modulators for psychiatric disorders.
Public Health Relevance: Severe forms of depression affect 2-5% of the US population, and mood disorders impact 7% of the world's population and rank among the top ten causes of disability. We are seeking to develop a new treatment for depression based on allosteric modulation of phosphodiesterase 4D.
Thesaurus Terms: 3'5'-Cyclic Ester Of Amp;Active Sites;Adenosine Cyclic 3',5'-Monophosphate;Adenosine Cyclic Monophosphate;Adenosine, Cyclic 3',5'-(Hydrogen Phosphate);Affect;Affective Disorders;Affinity;Amino Acids;Animal Model;Animal Models And Related Studies;Antidepressant Agent;Antidepressant Drugs;Antidepressants;Antidepressive Agents;Bdnf;Behavioral;Behavioral Assay;Binding;Binding (Molecular Function);Brain;Brain-Derived Neurotrophic Factor;C-Terminal;Catalytic Core;Catalytic Domain;Catalytic Region;Catalytic Site;Catalytic Subunit;Chemistry, Pharmaceutical;Clinical;Clinical Trials, Phase I;Clinical Trials, Phase Ii;Cognition;Cyclic Amp;Depression;Development;Drug Effect Disorder;Drugs, Investigational;Early-Stage Clinical Trials;Emesis;Encephalon;Encephalons;Fda Approved;Feedback;Generations;Genetic Polymorphism;Genetics-Mutagenesis;Goals;Human;Human, General;Hydrolysis;Investigational Drugs;Investigational New Drugs;Isoforms;Knock-In;Knock-In Mouse;L-Phenylalanine;Literature;Mgc34632;Mammals, Mice;Mammals, Primates;Man (Taxonomy);Man, Modern;Measures;Medicinal Chemistry;Mental Depression;Mental Disorders;Mental Health Disorders;Mice;Modeling;Molecular Biology, Mutagenesis;Molecular Interaction;Mood Disorders;Murine;Mus;Mutagenesis;N-Terminal;Nh2-Terminal;Nervous System, Brain;Pde;Pde4 Enzyme;Pde4b;Pdase Iv;Pharmaceutic Chemistry;Pharmaceutical Chemistry;Pharmacology;Phase;Phase 1 Clinical Trials;Phase 2 Clinical Trials;Phase I Clinical Trials;Phase I Study;Phase Ii Clinical Trials;Phenylalanine;Phenylalanine, L-Isomer;Phosphodiesterases;Polymorphism (Genetics);Polymorphism, Genetic;Population;Pre-Clinical Model;Preclinical Models;Primates;Protein Isoforms;Psychiatric Disease;Psychiatric Disorder;Pyrrolidone, 4-(3-Cyclopentyloxy-4-Methoxyphenyl)-2-;Radiation, X-Rays;Radiation, X-Rays, Gamma-Rays;Roentgen Rays;Rolipram;Sbir;Sbirs (R43/44);Schizophrenia;Schizophrenic Disorders;Site;Small Business Innovation Research;Small Business Innovation Research Grant;Structural Chemistry;Structure;Swimming;Tail Suspension;Testing;Toxic Effect;Toxicities;Universities;Unspecified Mental Disorder;Vomiting;West Virginia;X Ray;X-Radiation;X-Rays;Xrays;Active Site;Adenosine 3'5' Monophosphate;Alpha Helix;Aminoacid;Base;Biomarker;Brain Derived Neurotrophic Factor;Camp;Clinical Trial Phase I;Clinical Trial Phase Ii;Dementia Praecox;Design;Designing;Disability;Drug Action;Drug Discovery;Genetic Polymorphism;Improved;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Mental Illness;Model;Model Organism;Novel;Phase 1 Study;Phase 1 Trial;Phase 2 Study;Phase 2 Trial;Phase I Trial;Phase Ii Trial;Phosphodiesterase 4;Phosphodiesterase 4b;Phosphodiesterase 4d;Phosphodiesterase Iv;Phosphoric Diester Hydrolase;Polymorphism;Prevent;Preventing;Protocol, Phase I;Protocol, Phase Ii;Psychological Disorder;Public Health Relevance;Schizophrenic;Study, Phase Ii;Tool;Type 4 Cyclic Nucleotide Phosphodiesterase;University
