Download MendeleySmall molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.
St Jean, D.J., Ashton, K.S., Bartberger, M.D., Chen, J., Chmait, S., Cupples, R., Galbreath, E., Helmering, J., Hong, F.T., Jordan, S.R., Liu, L., Kunz, R.K., Michelsen, K., Nishimura, N., Pennington, L.D., Poon, S.F., Reid, D., Sivits, G., Stec, M.M., Tadesse, S., Tamayo, N., Van, G., Yang, K.C., Zhang, J., Norman, M.H., Fotsch, C., Lloyd, D.J., Hale, C.(2014) J Med Chem 57: 325-338
- PubMed: 24405213
- DOI: https://doi.org/10.1021/jm4016747
- Primary Citation of Related Structures:
4MQU, 4MRO - PubMed Abstract:
In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.
Organizational Affiliation:
Department of Therapeutic Discovery-Medicinal Chemistry, ?Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, ⊥Department of Pathology, #Department of Pharmaceutics Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California, 91320 and 360 Binney Street, Cambridge, Massachusetts, 02142, United States.
