Chapter 9:Pharmacokinetics and Metabolism of Compounds that Mimic Enzyme Transition States

Transition state analogue inhibitors (TSAI) are a class of competitive enzyme inhibitors that are designed to take advantage of this very high affinity interaction between an enzyme and the transition state of the reaction it catalyses. By mimicking the chemically unstable transition state, whilst being chemically stable themselves, TSAI can bind to the enzyme with much higher affinity than substrateThe group of transition state analogues discussed in this chapter in general have a relatively high PSA particularly when this value is compared with the PSA value of the top 200 selling drugs. This high polar surface area imparts a number of pharmacokinetic properties to this group of compounds particularly poor memrane permeability.Striking a balance between absorption and clearance is the main challenge for scientists looking to develop transition state analogues as therapeutic agents. However, the high potency (and often slow offset from the target) of these compounds means that if the balance between absorption and clearance can be achieved useful therapeutic agents can be discovered.