A Novel Class of Small Molecule Agonists with Preference for Human over Mouse TLR4 Activation
Fig 2
Optimization stages of Ugi products as TLR4 agonists.
*Human TLR-4 NFκB SEAP reporter assays; protocol as described in Methods. Data are reported as pEC50, or negative log of the EC50 values. **Clint rh / hm represents intrinsic clearance in presence of rat hepatocytes (μL/min/106 cells) and human microsomes (μL/min/mg protein). As a general guide, a value of <10 indicates good metabolic stability while >30 suggests that the compound is likely to be rapidly metabolized in vivo. †LogD represents the lipophilicity, whereby D is the octanol/water distribution coefficient at pH7.4. Thus a drug molecule with LogD >4 might be considered to be very lipophilic and therefore more likely to suffer from rapid metabolic turnover, poor solubility and receptor promiscuity; whereas a LogD range of 1–3 is more likely to be associated with optimal physicochemical and drug-like properties. ††Solubility was measured by dissolution of solid samples in buffer at pH 7.4.