Lead Development for Early Drug Discovery

Lead development requires identification of a lead small molecule with potential to be made into a clinical candidate. Once identified, the chemical structure of the lead compound is taken for chemical modifications to improve potency, selectivity or pharmacokinetic (PK) parameters.

Hit-to-lead phase

Improving the hit series to produce more efficacious compounds and potency can be observed using in vivo models.

Approaches:

  • Intensive SAR (structure–activity relationship) investigations
        — includes X-ray crystallography and NMR
  • Profiling of physicochemical and in vitro ADME properties
  • Solubility and permeability assessments
  • PK assessments in rats
Key In Vitro Assays
Aqueous solubility (for in vitro assays and for in vivo delivery of drug)
Log D7.4 (measure of lipophilicity thus movement across membranes)
Microsomal stability (compound clearance)
CYP450 inhibition (drug metabolizing enzyme and inhibition can cause toxicity)
Caco-2 permeability (permeability across intestinal epithelium, drug absorption from gut)
MDR1-MDCK permeability (to predict intestinal and brain permeability)
Hep G2 hepatotoxicity (effects of toxicity on human liver)
Cytotoxicity in suitable cell line (reduce chance of cellular toxicity in vivo)

Lead Optimization

Lead optimization is needed to improve the drawbacks in the lead structure, while maintaining its favourable biochemical properties

Approaches:

  • Ames test
  • High-dose pharmacology, PK/PD (pharmacodynamic) studies, dose linearity
  • Toxicological and chemical screens

Our goal is to help ensure only the strongest candidates make it past this stage of the drug identification and discovery process in order to fully optimize your pharmaceutical pipeline.

Products Supporting Lead Development

KitAlysis – high-throughput catalyst screening Catalytic methods of synthetic chemists, translated into an off-the-shelf screening system to quickly and efficiently identify or optimize suitable catalytic reaction conditions
HPLC Columns Include reversed phase and normal phase columns for biomolecules and large molecules (including ion exchange and gel filtration)
Analytical Sample Prep Extensive range of products for sample preparation with excellent absorptive, adsorptive, filtration and clarification properties.
ADME-Tox Innovative genetically engineered cell lines and validated assays designed to improve drug metabolism, transporter, and safety testing, as well as reagents, consumables, and labware
X-Ray Crystallography Kits to help researchers determine the optimal conditions for growing protein crystals reliably and reproducibly
Building Block Explorer Direct access to hundreds of thousands of reliably available synthetic building block products from selected global suppliers chosen for their consistent delivery and premium quality
Custom Synthesis For synthesizing lead-like or drug-like compounds (from small-scale to bulk quantities)
Late Stage Functionalization Reagents and Catalysts for Accelerated Chemical Diversification
NMR Widest selection of deuterated solvents/reagents, stable isotopes, NMR tubes/accessories, and innovative certified reference material (CRM) for quantitative NMR (qNMR)
TLC/Flash Chromatography plates For quick and convenient analysis of a broad spectrum of substances. As the leading supplier of TLC products, we offer an extensive portfolio
Gas Chromatography Complete line of packed GC columns and components
Chemical Synthesis Cross-Coupling, Fluorination, Metathesis and Non-Precious Metal Catalysis

 References

  1. Hughes, James P., et al. "Principles of early drug discovery." British journal of pharmacology 162.6 (2011): 1239-1249.
  2. Kuhn, Max, Ian Peers, and Stan Altan. Nonclinical statistics for pharmaceutical and biotechnology industries. Springer, 2016.
  3. Gashaw, Isabella, et al. "What makes a good drug target?." Drug discovery today 17 (2012): S24-S30.

 

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