1526937-49-4Relevant articles and documents
Small molecule disruptors of the Glucokinase-Glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles
St. Jean, David J.,Ashton, Kate S.,Bartberger, Michael D.,Chen, Jie,Chmait, Samer,Cupples, Rod,Galbreath, Elizabeth,Helmering, Joan,Hong, Fang-Tsao,Jordan, Steven R.,Liu, Longbin,Kunz, Roxanne K.,Michelsen, Klaus,Nishimura, Nobuko,Pennington, Lewis D.,Poon, Steve F.,Reid, Darren,Sivits, Glenn,Stec, Markian M.,Tadesse, Seifu,Tamayo, Nuria,Van, Gwyneth,Yang, Kevin C.,Zhang, Jiandong,Norman, Mark H.,Fotsch, Christopher,Lloyd, David J.,Hale, Clarence
, p. 325 - 338 (2014/02/14)
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.
