In addition, molecular weight and log D impact potency-efficiency calculations, allowing potency, clearance and permeability to be optimized simultaneously.
From this initial SAR examination, it was apparent that small structural changes greatly impacted potency; for example, removing the 4-chloro atom from 20 resulted in a ∼10 20-fold ∼10 20-foldency in the unsubstituted pyrimidine, 21.
Due to potential impact on potency and immunogenicity, it is important to understand the formation mechanism of such variants so that appropriate control strategies can be implemented to assure product quality.
These results clearly demonstrate that the substitution of cysteine residues in the CT domain has a significant impact on potency, but substituting cysteine residues in both the TM and CT domains has a synergistic effect on potency of the rHA.
However, the V138A3.36 mutation of TM3OX2 had no impact on potency (see Table 1).
Our results showed that modification on steroid core > modification on lactone ring > modification on sugar in decreasing impact on potency.
In the case of OX1, F5.42 interacts with H26 of OxA that, based on the SDM experiments, has an only moderate impact on potency (see Figure 6A).
The SAR profile (pattern of structural requirement for activity modulation) for antimigratory activity is: modification on steroid core > modification on lactone ring > modification on sugar in decreasing impact on potency.
However, this tyrosine in the E09 VH CDR3 loop, could be mutated to several other side chains without any major impact on potency (data not shown), indicating that it was not a critical residue for signal transduction.
Initial screens indicated that the invasion inhibitory IC50 differed between azithromycin prepared in ethanol (10 μM) or DMSO (38 μM), suggesting that choice of vehicle can impact azithromycin potency in vitro.
These data also suggest that changing end-of-shelf-life specifications such that vaccine at expiry contains one-half the recommended antigen dose, is unlikely to impact clinical potency, but would allow for the extended use of available vaccine stocks.
