This is the process whereby ‚”Hits” from screening are transformed into ‚ “Leads” that can be then used for “Lead Optimisation” This could be a single screening hit or homologous group of hits, or lead from literature. But High-through-put screening can deliver multiple discrete series the critical decision is which hit(s) to focus on. Some companies use the term Hit to Lead (het2lead) group.

• Tightly integrated with dedicated biology and ADME.
• Parallel Biological and “Developability” evaluation essential
• Dense data matrix
• High degree of automation, computational analysis
• Cycle time is key to success, need integration with in vitro ADME and in silico tools
• Computational tools can make a significant impact
• For out-sourcing to be successful would ideally need CRO to have all chem/biol/comp/ADME

What makes a good Lead

• Ideally multiple discrete series from High Throughput Screening
• Confirmed activity and structure using fresh, pure sample
• < 3uM in vitro, appropriate functional activity
• Reversibility
• Key assays available for selectivity
• Singletons need to be confirmed by small library synthesis
• Need to be 5-10 compounds to confirm options for diveristy
• No undesirable functional groups or chemical reactivity
• Toxicologically suspect groups
• Scope for expansion (IP position and suitable chemistry)
• Tractable physical properties
• Physicochemical properties
  • Molecular Weight, Solubility, LogP/D , pKa
• ADME profiles available for representative analogues
• Particularly oral absorption, solubility for i.v. and CNS penetration as appropriate.
• Evidence that any ADME issues are tractable

Remember Potency is usually the most easily optimised property