Property based optimisation of glucokinase activators – discovery of the phase IIb clinical candidate AZD1656

Property-Based Design in the Optimisation of Benzamide Glucokinase Activators

“…We were also able to demonstrate that the neutral compounds (27) and (28) showed no antagonism of RAR-a (IC 50 >30 mM), giving further weight to our association of this target with testicular toxicological findings. We were subsequently able to use computational modelling to provide a structural basis to our observations.…”

“…[28]-Adapted and reproduced by permission of The Royal Society of Chemistry significantly improved the effect on AUC reduction at equivalent doses in free feeding Zucker rat glucose profiles (Figure 1.20). Metabolite identification studies revealed that one route of metabolism of (45) is demethylation of the methoxy ether to form the corresponding alcohol.…”

“…In these experiments, F abs , in both dog and monkey, and human intestinal flux were all greater than observed in rat. Nevertheless, we determined that there remained a potential risk that human absorption might ultimately prove sub-optimal and variable across patients [28].…”

“…Furthermore, subsequent testing of the fragment in more relevant genotoxicity assays such as rat bone marrow micronucleus and rat liver unscheduled DNA synthesis tests revealed no concerns. However, the generation of the Ames positive result meant that front-loaded genotoxicity tests would need to be included in any clinical development plan [28]. While neither the permeability nor the Ames activity of the 1-methyl-3-aminopyrazole fragment was believed to preclude development of the compound, we judged that they could pose hurdles to rapid clinical progression.…”

“…The compound showed a benign safety profile and was selected for clinical development. Compound (45) was given the internal identifier AZD1656 and rapidly overtook AZD1092 (30) as it progressed to human trials [28].…”