Drug Design 2 - Applied Bioinformatics Group

Failure in Late Development
• 90% of all drug candidates fail
between discovery and
introduc%on to the market
• The late development phases are
the most expensive phases
• In a study from 1988, Pren%s et
al. found that in more than 60%
of the cases, poor
pharmacokineDc (PK) or
toxicological properDes were the
cause
Failure in Late Development
31%
Reason for Failure
6%
41%
22%
Market
Toxicity
PK
Efficacy
Prentis et al., Br. J. Clin. Pharmacol. 1988, 25, 387-396.
• More recent studies find that this problem has changed since
• Currently PK and bioavailability play a minor role
• This is mostly due to improved tes%ng, but quite likely also due to
improved computa%onal models for these proper%es
• The problem of toxicity has increased as well, we will discuss
methods for addressing this issue later
Consequences for Discovery
Biol.
Data
Lead ID
• Restrict search space to candidates with good
pharmacokineDc properDes
Kola & Landis, Nat Rev Drug Discov. 2004;3(8):711-5.
Target ID Lead ID Optimization Trials Approval
• Exclude compounds with poor proper%es from virtual
screening campaigns
Lead opDmizaDon
• Improve efficacy (µM ! nM)
• Reduce side effects
• Improve pharmacokineDcs