Discovery Teams
At the Warren Center for Neuroscience Drug Discovery, our Discovery Teams form the backbone of our translational research efforts. These highly collaborative groups—spanning medicinal chemistry, molecular pharmacology, DMPK, and behavioral pharmacology—combine deep expertise with advanced technologies to drive every stage of the drug discovery process. From target validation to in vivo proof of concept, our integrated approach allows for rapid iteration and seamless progression toward clinical candidates.
Medicinal Chemistry
Objective:
Develop small molecule in vitro probes, in vivo tool compounds and IND-ready preclinical candidates through high-throughput, iterative medicinal chemistry
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Matrix/Parallel library synthesis
Modern Synthetic Technologies: Microwave (Biotage), Photo-redox and Electrochemical synthesis
High-throughput Purification Technologies: (Waters LCMS, - Gilson HPLC, Biotage, Teledyne Isco)
Supercritical Fluid
Chromatography (SFC) for chiral HPLC (analytical and preparative)
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Specially curated chemical building block collection for neuroscience targets.
Real-time incorporation of in vitro and in vivo DMPK data into SAR.
Development of intellectual property (IP) in parallel with tools for academic discovery.
Molecular Pharmacology and Biology
Objective:
Provide primary screening, assay development, high-throughput screening (HTS) and detailed in vitro pharmacological analysis of small molecule ligands.
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Hamamatsu FDSS (µCell) screening platform
Agilent BRAVO liquid handlerBeckman Coulter ECHO 650 acoustic liquid handler
EnVision 2105 Multimode Microplate Reader
Ca2+ mobilization fluorescence assay
GIRK/Thallium Flux assay
Radioligand displacement assays
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Dotmatics Knowledge Solutions for cloud-based analysis and storage of assay data.
Triplicate Screening technology to capture 3 modes of ligand pharmacology in one 4 min assay.
Weekly data generation and reporting to inform SAR for the next round of screening.
Drug Metabolism and Pharmacokinetics (DMPK)
Objective:
Support the WCNDD’s drug discovery efforts by providing comprehensive in vitro and in vivo ADME (Absorption, Distribution, Metabolism, and Excretion) services, including metabolic stability, protein binding, permeability, CYP inhibition, pharmacokinetics, and human dose prediction.
Establish a DMPK team with capabilities uncommon in academic settings, modeled after the structure and efficiency of a mid-sized biotech company.
Deliver full in vitro and in vivo ADME profiling to de-risk preclinical candidates and facilitate early “Go/No-Go” decisions.
Understand mechanisms of drug clearance and pharmacokinetic/pharmacodynamic (PK/PD) relationships to maximize on-target efficacy.
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The primary goal of in vitro ADME (Absorption, Distribution, Metabolism, and Excretion) studies is to evaluate the pharmacokinetic properties of drug candidates early in the development process. These studies help predict how a drug will behave in the human body, guide chemical optimization, and assess potential drug-drug interactions, ultimately aiding in the selection of viable candidates for further investigation.
Protein Binding (Plasma and Brain Homogenate)
Metabolite Identification (MetID) Assay (HLM or Hepatocytes)
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The main aim of in vivo DMPK (Drug Metabolism and Pharmacokinetics) studies is to assess how a drug behaves within a living organism, typically animal models. These studies provide crucial insights into absorption, distribution, metabolism, and excretion profiles under physiological conditions, helping predict human pharmacokinetics and supporting dose selection and safety evaluations for clinical trials.
Rat IV PK PBL Cassette
Rat IV PO PK discrete studies
Rat/Mouse PO PBL exposure studies
NCA Analysis
PK/PD relationship studies (Rat and Mouse)
MED and MTD to establish therapeutic index
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Liquid handling and robotization streamline workflows by automating repetitive tasks, such as sample preparation and reagent dispensing, reducing manual labor and minimizing errors. These technologies enable higher precision and consistency, allowing researchers to process larger sample volumes in less time. At the WCNDD, we use the following equipment.
Triple Quad 4500 mass spectrometers
Qtrap 5500 and 6500+ mass spectrometers
Sciex Automated MRM Discoverer software
Orbitrap Thermo Lumos Fusion mass spectrometer
Tecan Evos liquid handler
Agilent Bravo with BenchCel workstation
Beckman Echo 650 liquid handler
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First-in-human dose prediction involves integrating data from preclinical studies to estimate a safe starting dose for clinical trials. This involves analyzing pharmacokinetics, pharmacodynamics, and toxicity profiles from in vitro and in vivo studies, and scaling doses to humans using allometric or physiological models.
Allometric scaling
IVIVE
Behavioral Pharmacology
Objective:
Provide pharmacological characterization of small molecule ligands in established preclinical models of central nervous system (CNS) disorders including schizophrenia (Sz), Parkinson’s Disease (PD), dystonia, and Alzheimer’s Disease (AD)
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Assay evaluating antipsychotic-like activity: Amphetamine- or MK-801 Induced hyperlocomotion, PPI, CAR
Assays to assess cognitive function: NOR, conditioned fear, RAM, MWM
Assays to evaluate efficacy in movement disorders: HIC, 6-OHDA lesion forelimb asymmetry, rotarod, automated gait analysis
Assays to evaluate pain: von Frey, Hargreaves, formalin test
Assays to assess addiction: Self administration, CPP
Genetic/humanized rodent models of Alzheimer’s disease
Dosing/collection of in life PK samples for DMPK
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Develop strong pharmacokinetic/pharmacodynamic relationships in various animal models for GPCRs and related targets.
Support biomarker strategies (i.e. EEG, phMRI, PET) in preclinical models.
Evaluate early stage, preclinical toxicology and safety pharmacology for pre-IND candidates.