Lead compound

This article is about the pharmaceutical concept. For compounds containing the element lead, see Lead compounds. For use of lead in structures, see Lead § Applications.

A lead compound (/ˈliːd/, i.e., a "leading" compound; not to be confused with various compounds of the element lead) in drug discovery is a chemical compound that has pharma­co­logical or biological activity likely to be therapeutically useful, but may never­the­less have suboptimal structure that requires modification to fit better to the target; lead drugs offer the prospect of being followed by "back-up" compounds. The chemical structure serves as a starting point for chemical modifications in order to improve potency, selectivity, or pharma­co­kinetic parameters. Furthermore, newly-invented pharma­co­logically active moieties may have poor druglikeness and may require chemical modification to become "drug-like" enough to be tested biologically or clinically.^[1]

Lead compounds are sometimes called developmental candidates.^[1] This is because the discovery and selection of lead compounds occurs prior to preclinical and clinical development of the candidate.

Discovering lead compounds

Discovery of a drugable target

Before lead compounds can be discovered, a suitable target for rational drug design must be selected on the basis of biological plausibility, or identified through screening potential lead compounds against multiple targets.^[1] Drug libraries are often tested by high-throughput screenings (active compounds are designated as "hits") which can screen compounds for their ability to inhibit (antagonize) or stimulate (agonize) a target of interest as well as determine selectivity for these targets.^[1]

Development of a lead compound

A lead compound may arise from a variety of different sources. Lead compounds are found by characterizing natural products, employing combinatorial chemistry, or by molecular modeling as in rational drug design.^[2] Chemicals identified as "hits" through high-throughput screening may also become lead compounds.^[1]

Once a lead compound is selected, it must undergo lead optimization, which involves making the compound more "drug-like."^[1] This is where Lipinski's rule of five comes into play, sometimes also referred to as the "Pfizer rule" or simply as the "rule of five".^[3] Other factors, such as the ease of scaling up the manufacturing of the chemical, must be taken into consideration as well.^[3]

See also

• Drug development – Process of bringing a new pharmaceutical drug to the market
• Drug design – Invention of new medications based on knowledge of a biological target
  • Rational drug design – Invention of new medications based on knowledge of a biological targetPages displaying short descriptions of redirect targets
• Drug discovery hit to lead – Stage of drug discoveryPages displaying short descriptions of redirect targets
  • Lead optimization – Stage of drug discoveryPages displaying short descriptions of redirect targets