THERAPEUTIC TEAMS

Central Nervous System Disorders: Neuroscience
The Neuroscience team is focused on the identification of new targets as potential opportunities for therapeutic intervention in the treatment of CNS disorders such as those involving sleep/wake, addiction, and central regulation of metabolism. The therapeutic team's primary approach involves the identification of novel targets using molecular or genomic techniques with special emphasis on GPCRs. Following the identification of a new target, high-throughput screening is applied to provide lead compounds, which then become the subject of an iterative medicinal chemistry approach to obtain small molecule drug candidates. The team concentrates on quantitative in vivo measures of drug response such as sleep/EEG, imaging, and metabolic profiling of candidate compounds that may eventually translate as biomarkers to clinical trials.

Inflammatory Diseases: Immunology and Inflammation
The Immunology and Inflammation teams investigate new or overlooked targets in the areas of inflammation and immunosuppression. By concentrating on key regulatory pathways and identifying druggable targets within those pathways, the teams select drug targets implicated in immune-mediated inflammatory diseases ranging from allergies and asthma to rheumatoid arthritis and lupus. Input is solicited from scientists of all disciplines, from bioinformaticists and molecular modelers to medicinal chemists and in vivo pharmacologists, at the earliest stages of target selection and hit identification. This multi-disciplinary approach is maintained and expanded throughout the lead optimization process. Current targets being explored include proteases and kinases involved in antigen presentation and stress response signaling, and GPCRs implicated in localized inflammatory responses and T-cell activation. The teams' overriding goal is to deliver new, high-quality drug candidates and provide continuing scientific support for the development of those drug candidates through Phase II clinical studies.

Site resources for chemical lead identification and optimization are embedded in the Immunology Chemistry team. Special emphasis is placed on the identification, implementation, and dissemination of new instrumentation and methodologies that can aid in more efficient data management as well as design, synthesis, and purification of compounds.

Inflammatory Diseases: Pain & Related Disorders
The mission of the Pain & Related Disorders team is to develop mechanistically novel, safe, and effective treatments for pain. There is a substantial unmet medical need for new treatments for disorders such as neuropathic pain, arthritis pain, and visceral pain, as well as for non-opioid analgesics. The team is interested in the sensitizing effects of inflammatory processes on peripheral nociceptors, as well as central neuroinflammatory contributions to both sensory disturbances and disease progression. The team uses a pharmacokinetic-pharmacodynamic approach to support new compound selection, and its programs are extensively biomarker driven.

Metabolic Diseases: Internal Medicine
Since its inception at La Jolla in 2000, the Internal Medicine team has focused largely on basic biological research, drug discovery, and progression through early clinical development of peptide hormones and novel GPCR receptor antagonists for the treatment of gastrointestinal and metabolic diseases. These efforts are supported by a closely-knit group of pharmacologists and chemists working in a team-based drug discovery setting that commences with biological target identification and assay development, and continues into the clinic. Publication and external oral presentations are strongly encouraged.

ENABLING TEAMS

Analytical Chemistry
The Analytical Chemistry team supports the site's therapeutic teams, solving chemical structures and purifying important compounds in a definitive and timely manner with methods such as NMR spectroscopy, LC/MS, GC/MS, HPLC, and SFC. The team's responsibilities include acquiring, upgrading, integrating, and maintaining complex analytical instruments. Team members research and publish on new analytical methods and technologies, and collaborate with therapeutic teams on projects that require special analytical support.

Biological Enabling Research Technologies (BERT)
The five groups comprising BERT support many different aspects of the in-house drug discovery process:

Genomic Technologies uses microarrays and quantitative PCR to measure mRNA levels, and also has the capability to run SNP chips for pharmacogenomic studies. The group evaluates novel genomic technologies and works with discovery scientists, toxicologists, development teams, and geneticists at several J&J sites.

High-Throughput Screening collaborates with therapeutic teams to develop HTS assays for new targets, and carries out screening campaigns to identify new leads for medicinal chemistry. The group exploits modern high-throughput robotics to screen an in-house compound collection for activity against new targets, and is equipped to handle assays in most current formats.

Drug Metabolism and Pharmacokinetics performs bioanalysis and DMPK profiling of compounds. In vitro assays conducted by the group include metabolic stability in microsomes, cytochrome P450 inhibition, protein binding, and metabolic pathway profiling. The group works closely with therapeutic teams to understand how compound structural features influence properties important for a compound's pharmacokinetic profile, with the goal of accelerating lead optimization, and provides data used for compound development decisions.

Developability characterizes compound physicochemical properties, and develops and prepares formulations. The group works closely with therapeutic teams during compound optimization and serves as an interface with the chemical pharmaceutical function in Development.

Compound Logistics Center (CLC) maintains an inventory of compounds synthesized in local chemistry programs. The group also works with global CLC counterparts to grow the corporate screening collection and is responsible for site-wide distribution of compounds used for in-house high-throughput screening, as well as reagents used in chemistry.

Bioinformatics
The multidisciplinary Bioinformatics team forms the core of the J&JPRD Bioinformatics Center of Excellence, and is responsible for setting global directions for analyzing, managing, and storing biological data. The team conducts research in data mining and algorithm development. A Software Development arm develops and maintains global project management and communication software, as well as scientific applications. The team's Data Analysis arm assists therapeutic teams with sequence analysis, microarray analysis, biomarker discovery, target identification and validation, and general data analysis needs. In addition, Data Analysis works closely with the BERT team, providing support in microarray manufacturing and processing QC, and evaluation of commercial microarray technologies.

Computer Aided Drug Discovery (CADD)
The CADD team uses computational approaches such as cheminformatics and molecular modeling to assist the drug discovery process in the areas of lead identification, lead optimization, and ADME/toxicity profiling. The team develops and deploys cheminformatics tools and technology that permit discovery scientists to query, retrieve, and analyze chemical and biological data, thereby enabling the scientists to make key decisions on the directions of their projects. CADD team members apply docking, energy minimization, pharmacophore analysis, QSAR, and other molecular modeling methods to identify new lead compounds and provide rational structure-based approaches to lead refinement. By developing in silico models that provide rapid predictions of ADME/toxicity properties, CADD identifies potential liabilities of lead compounds and provides insights for rectifying those liabilities before a candidate compound enters Early Development. Finally, the team actively evaluates new computational chemistry methods and approaches for drug discovery with the intent of implementing them on discovery projects whenever practical.

Scale-Up Chemistry
The Scale-Up Chemistry team devises multi-gram chemical syntheses for the site's small-molecule drug discovery teams, moving new molecular entities (NMEs) rapidly towards Early Development. The team synthesizes candidate drug substances in sufficient quantities (100-250 g) for all in vivo pharmacological and toxicological experiments. Scale-up Chemistry strives for efficient, scaleable routes that Chemical Development could potentially use for GMP syntheses. By acting as a conduit for synthesis technology, sourcing of intermediates, physical forms of drug substance, salt selection, and other critical information, the team forms an important link between drug discovery and Early Development.

EARLY DEVELOPMENT

The diverse scientists and physicians comprising the site's Early Development team represent many functions all working together to move NMEs into and through the early stages of clinical development. The team specializes in clinical proof-of-concept for compounds targeting inflammatory diseases. It partners with other R&D divisions to design programs that assess the safety, tolerability, and efficacy of new molecular entities, and strives to generate data that allow for better understanding of the strengths and limitations of each compound, with the ultimate goal of advancing drug candidates into Phase III and to the market.


Glossary

ADME CNS DMPK EEG GC/MS GMP GPCRs HPLC HTS LC/MS mRNA NMR PCR QC QSAR SFC SNP T-cell

absorption, distribution, metabolism, and excretion central nervous system drug metabolism and pharmacokinetics electroencephalogram gas chromatography-mass spectrometry good manufacturing practices G protein-coupled receptors high performance liquid chromatography high-throughput screening liquid chromatography-mass spectrometry messenger ribonucleic acid nuclear magnetic resonance polymerase chain reaction quality control quantitative structure-activity relationships supercritical fluid chromatography single nucleotide polymorphism thymus lymphocyte cell

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