Encyclopedia of Cancer

Living Edition
| Editors: Manfred Schwab

Lead Optimization

Living reference work entry
DOI: https://doi.org/10.1007/978-3-642-27841-9_3298-3

Definition

The synthetic chemical modification of a biologically active molecule to address pharmacokinetic, pharmacodynamic, and toxicologic issues in order to enable its clinical utility.

Characteristics

Drug discovery activities that occur prior to lead optimization, such as the choice of target, assay development, high-throughput screening, and early molecular optimization and testing, are typically referred to as lead generation. Leads typically have been somewhat optimized for their molecular properties (solubility, removal of covalent modifiers, chemical stability), have been subjected to in vitro assays to predict their pharmacokinetic properties (Caco-2 flux, liver microsomal stability, protein binding, inhibitory activity toward cytochrome P450 isoenzymes(CYP450s)), possess reasonable in vitro and cellular potencies toward the molecular target, and have been subjected to some selectivity measurements (kinase selectivity screen and a broad receptor/transporter selectivity...

Keywords

Oral Bioavailability Reactive Metabolite Lead Optimization Idiosyncratic Drug Reaction Flavin Monooxygenases 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. Balani SK, Miwa GT, Gan LS et al (2005) Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Curr Top Med Chem 5:1033–1039CrossRefPubMedGoogle Scholar
  2. Doss GA, Baille TA (2006) Addressing metabolic activation as an integral component of drug design. Drug Metab Rev 38:641–649CrossRefPubMedGoogle Scholar
  3. Nassar AEF, Lopez-Anaya A (2004) Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov Devel 7:126–136PubMedGoogle Scholar
  4. Nikitenko AA (2006) Compound scale-up at the discovery-development interface. Curr Opin Drug Discov Devel 9:729–740PubMedGoogle Scholar
  5. Picard S, Lacroix P (2003) QT interval prolongation and cardiac risk assessment for novel drugs. Curr Opin Investig Drugs 4:303–308PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Johnson & Johnson Pharmaceutical Research & DevelopmentSpring HouseUSA