Inspire Pharmaceuticals, Inc. - Research and Preclinical Development

MOLECULAR PHARMACOLOGY - The science that studies, at the molecular level, the action of drugs on biological systems.

PRECLINICAL DEVELOPMENT - Compounds being studied for a specific therapeutic application that have not yet been tested in humans, but are actively being studied in tissue or animal models.

PRECLINICAL - Studies conducted in animals or tissues prior to studies conducted in humans.

P2Y RECEPTOR - P2Y receptors are protein molecules expressed on the surface of cells. Receptors bind specific types of molecules called ligands (large number of marketed drugs are receptor ligands). This binding activates specific processes within the cell. A simple way to think of a drug binding to a receptor is the analogy of a key fitting a lock. A drug (a key) binds to a receptor (a lock) and activates specific processes within the cell. Inspire's drug candidates bind to a particular type of receptor called the P2Y2 receptor (one type of P2Y receptor) and activate the processes of mucosal hydration and mucociliary clearance.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

Overview of Research and Preclinical Development
Our scientists have specific expertise and proprietary knowledge relating to the design and synthesis of P2 receptor agonists and antagonists, including P2Y2 agonists, P2Y12 antagonists and P2X antagonists. We have invested in state-of-the-art equipment and laboratory space for performing synthetic chemistry, determination of compound structure and receptor location and function identification. Our research effort is focused on conducting studies using cell-based scientific tests that measure biological activities caused by stimulation or blocking of P2 receptors, to identify new compounds that specifically and selectively bind to members of the P2 receptor family. These tests enable us to identify agonists and antagonists that act at specific receptor subtypes and demonstrate a level of specificity and activity that merits further investigation. We use data from these tests to design and synthesize compounds specific to each P2 receptor subtype that can be advanced to clinical trials.

By screening against several P2 receptor subtypes, we have been able to identify agonists and/or antagonists that interact preferentially with a specific receptor subtype. Several proprietary compounds, including new chemical entities, with promising stability and metabolic profiles are being actively explored. We intend to conduct further preclinical development studies to advance such proprietary compounds to project status, if appropriate. These compounds will then be targeted to the treatment of new disease areas, as identified through our strategic planning process.

We obtain access to chemical libraries through our own proprietary chemistry, commercial sources and corporate agreements. The chemicals are screened for both agonist and antagonist activity. Our chemistry department also assists in the development of analytical protocols used by contract service organizations for analysis of a drug substance, clinical trial material and drug stability studies which will be incorporated into IND and NDA filings.

We use sponsored research agreements to investigate specific biological processes to augment our technology platform. We have sponsored research agreements at major universities. We use contract research organizations for toxicology and most preclinical studies required for regulatory submissions, such as IND applications.

URIDINE TRIPHOSPHATE - A naturally occurring compound that has been shown to activate the P2Y2 receptor.

NUCLEOTIDE - A molecule of structure similar to building blocks of nucleic acids (DNA and RNA). Nucleotides via interaction with specific receptors stimulate various processes within the cell.

INVESTIGATIONAL NEW DRUG application - an application filed with the Food and Drug Administration.

P2Y RECEPTOR - P2Y receptors are protein molecules expressed on the surface of cells. Receptors bind specific types of molecules called ligands (large number of marketed drugs are receptor ligands). This binding activates specific processes within the cell. A simple way to think of a drug binding to a receptor is the analogy of a key fitting a lock. A drug (a key) binds to a receptor (a lock) and activates specific processes within the cell. Inspire's drug candidates bind to a particular type of receptor called the P2Y2 receptor (one type of P2Y receptor) and activate the processes of mucosal hydration and mucociliary clearance.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

History of Research at Inspire

The First Inspire Program - UTP
Inspire's first lead clinical development compound was UTP, a potent, naturally occurring nucleotide, that was successfully administered to subjects under an investigator sponsored IND filing with the FDA. Inspire scientists quickly realized that UTP was an excellent drug candidate, and that its usefulness could be further enhanced by improving stability, thus eliminating the need for refrigeration of the compound.

ANALOG - A compound that resembles another in structure and activity.

DINUCLEOTIDE - A new class of nucleotides that have a dumbbell-like structure with nucleosides on the ends connected by a phosphate backbone.

A medicinal chemistry campaign was launched to find analogs of UTP that were chemically stable while retaining potency. Together with UNC scientists, Inspire discovered and synthesized INS365, a new class of P2Y2 receptor agonists based on the dinucleotide core structure that imparts a surprising amount of chemical stability, with a shelf life estimated at > 2 years.

SPUTUM - Thick airway secretions that are expectorated or discharged from the lungs.

PRECLINICAL DEVELOPMENT - Compounds being studied for a specific therapeutic application that have not yet been tested in humans, but are actively being studied in tissue or animal models.

URIDINE TRIPHOSPHATE - A naturally occurring compound that has been shown to activate the P2Y2 receptor.

With the INS365 discovery in hand, Inspire's project team worked rapidly to get this new molecule into human clinical testing. The first clinical study of INS365, performed in the UK, was conducted a short 12 months later.

At the same time, the Research and Preclinical Development scientists began uncovering new therapeutic uses for the new generation P2Y2 receptor agonist INS365. Research demonstrated that the compound activated the release of fluid and tear components onto the ocular surface and the idea for using INS365 for dry eye was rapidly advanced.

CHLORIDE SECRETION - Specifically pertaining to Cystic Fibrosis, the movement of chloride ions to the surface of the lungs, stimulating the hydration of the lung surface, which is necessary for lung protection and health.

P2Y RECEPTOR - P2Y receptors are protein molecules expressed on the surface of cells. Receptors bind specific types of molecules called ligands (large number of marketed drugs are receptor ligands). This binding activates specific processes within the cell. A simple way to think of a drug binding to a receptor is the analogy of a key fitting a lock. A drug (a key) binds to a receptor (a lock) and activates specific processes within the cell. Inspire's drug candidates bind to a particular type of receptor called the P2Y2 receptor (one type of P2Y receptor) and activate the processes of mucosal hydration and mucociliary clearance.

CHLORIDE CHANNEL - Specifically pertaining to Cystic Fibrosis, the protein responsible for the transportation of chloride ions to the surface of the lungs, stimulating the hydration of the lung surface, which is necessary for lung protection and health

METABOLISM - The process by which a substance is broken down into other substances within the body.

Next Generation Compound - denufosol
In the 90's, as the genetic defect of cystic fibrosis (CF) was unraveled, researchers were puzzled by the fact that the CF Mouse, i.e. a genetically altered mouse with the defect of CF, does not develop lung disease. Part of the reason for this unexpected result is the fact that the mouse lung uses an alternative mode of chloride secretion--one that is normally quiescent in man. Researchers at UNC Chapel Hill CF Research Center discovered that activation of the P2Y2 receptor turns on this alternative chloride channel, thus circumventing the genetic defect that causes the disease. Since P2Y2 agonist therapy for CF requires going head to head with a genetic defect that works against the lung 24 hours a day, Inspire's challenge was to discover a long acting P2Y2 agonist that is resistant to metabolism by the "enzymatic soup" in the CF lung.

Click here for airway surface animation/audio

NUCLEOTIDE - A molecule of structure similar to building blocks of nucleic acids (DNA and RNA). Nucleotides via interaction with specific receptors stimulate various processes within the cell.

DINUCLEOTIDE - A new class of nucleotides that have a dumbbell-like structure with nucleosides on the ends connected by a phosphate backbone.

SPUTUM - Thick airway secretions that are expectorated or discharged from the lungs.

PRECLINICAL - Studies conducted in animals or tissues prior to studies conducted in humans.

MUCUS TRANSPORT - The movement of mucus on surfaces where it plays a role in hydrating and lubricating (e.g., mucous membranes such as the eye, lung, mouth, sinuses).

MUCOCILIARY CLEARANCE - The process by which mucosal surfaces such as the lungs and sinuses are cleared of particles such as dust, bacteria and viruses by the action of cilia. Cilia are small, hair-like projections that move in a waving motion to "sweep" debris away from the mucosal surface. The cilia are suspended in a layer of fluid, which allows them to move freely. Both the fluid layer and the movement (or beat) of the cilia are essential for the health of mucosal surfaces such as the lungs and sinuses.

MUCOSAL HYDRATION - the process by which the body moistens and lubricates mucosal surfaces such as the eyes, sinuses and lungs. Specific cells on mucosal surfaces facilitate the movement of fluids (e.g., water, mucin and lipids) onto these surfaces. Proper hydration of mucosal surfaces is essential for the health of the mucosal tissues.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

Inspire's expertise in the synthesis of nucleotides and dinucleotides led to the discovery of next generation P2Y2 agonists with a much greater metabolic stability and thus a longer duration of action. The new compound, INS37217, was chosen for development in treating cystic fibrosis lung disease instead of INS365 due to its enhanced resistance to metabolism by enzymes in CF sputum and on the cell surface. Denufosol, with a duration of action of > 8hrs in preclinical animal models of mucus transport, circumvents the genetic defect present in CF patients by activating an alternative chloride secretion channel, resulting in normalization of the mucus hydration and enhanced mucociliary clearance.

ELECTROPHYSIOLOGY - The study of the electrical properties of tissues and their functions.

P2Y RECEPTOR - P2Y receptors are protein molecules expressed on the surface of cells. Receptors bind specific types of molecules called ligands (large number of marketed drugs are receptor ligands). This binding activates specific processes within the cell. A simple way to think of a drug binding to a receptor is the analogy of a key fitting a lock. A drug (a key) binds to a receptor (a lock) and activates specific processes within the cell. Inspire's drug candidates bind to a particular type of receptor called the P2Y2 receptor (one type of P2Y receptor) and activate the processes of mucosal hydration and mucociliary clearance.

RPE - The cellular tissue that lines the back of the eye, directly behind the retina.

HIGH THROUGHPUT SCREENING - A method for testing a large number of molecules for biological activity in very rapid fashion.

Informatics
All Biology and Chemistry information at Inspire are stored in Oracle and organized and accessed through ActivityBase (IDBS, Cambridge, UK). Our system provides Inspire scientists and collaborators with advanced statistical and analysis algorithms and sophisticated data search and visualization capabilities that allow full utilization and access of all the data and available information in a highly integrated fashion.

<Deeper Science on screening assays>

LEAD DISCOVERY - The practice of research whereby scientists search for compounds that have the activity and characteristics desired for treating a specific condition. Once identified, the compound is called a "lead".

OPTIMIZATION - The practice of research whereby scientists further study a "lead" compound and alter it to increase its potency or decrease its undesirable effects.

NUCLEOSIDE/NUCLEOTIDE SYNTHESIS - The creation of molecules of structures similar to the "pieces" that make up RNA and DNA. These molecules by their actions on specific receptor proteins stimulate various processes within the cell.

COMPUTATIONAL CHEMISTRY - The analysis of computer-generated molecular structures.

CHROMATOGRAPHIC AND SPECTROMETRIC INSTRUMENTATION - Instruments that enable a chemical mixture to be analyzed and separated into its component parts.

NUCLEOTIDE - A molecule of structure similar to building blocks of nucleic acids (DNA and RNA). Nucleotides via interaction with specific receptors stimulate various processes within the cell.

DINUCLEOTIDE - A new class of nucleotides that have a dumbbell-like structure with nucleosides on the ends connected by a phosphate backbone.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

MOLECULAR PHARMACOLOGY - The science that studies, at the molecular level, the action of drugs on biological systems.

DRUG EVALUATION- Compounds being studied for a specific therapeutic application that have not yet been tested in humans, but are actively being studied in tissue or animal models.

NUCLEOTOIDS - Nucleotide-like substances, which preserve their parent nucleotide function and are designed to have enhanced properties such as longer half lives and oral bioavailability.

Chemistry
Inspire has assembled a core chemistry function with more than 100 years collective experience in lead discovery and optimization, nucleoside/nucleotide synthesis, and computational chemistry. The group is well equipped with state-of-the-art chromatographic and spectrometric instrumentation for purification and analysis of nucleotides and related compounds. With this depth of experience and resources, the group discovered a new platform of dinucleotides that act as potent P2Y receptor agonists, and has amassed one of the most extensive libraries of dinucleotides and dinucleotide derivatives in the world. This platform has resulted in 21-awarded patents and many new chemical entities, which are currently in four active development programs. Working closely with Molecular Pharmacology and Drug Evaluation to validate and develop new targets, Chemistry is also engaged in the discovery and optimization of nucleotoids and non-nucleotide compounds.

<Deeper Science on nucleotoids>

Page last updated: 29-Mar-2007