| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1364151 | Bioorganic & Medicinal Chemistry Letters | 2009 | 4 Pages |
A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.
Graphical abstractUtilizing parallel synthesis and a high-throughput in vitro micronucleus assay enabled the identification of 10g, a highly DPP-IV selective compound with an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.Figure optionsDownload full-size imageDownload as PowerPoint slide
