Correction to Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

作者: Andrews, Kristin L. ; Hale, Clarence ; Fotsch, Christopher ; Cupples, Rod ; Michelsen, Klaus ; Zhang, Jiandong ; Helmering, Joan ; Bryan, Marian C. ; Poon, Steve F. ; Kurzeja, Robert J. M. ; Chen, Jie ; Wahl, Robert C. ; Sivits, Glenn ; Chen, Michelle ; Pennington, Lewis D. ; Chen, Kui ; Van, Gwyneth ; Lloyd, David J. ; Ashton, Kate S. ; St. Jean, David J. Jr. ; Chmait, Samer ; Vonderfecht, Steve L. ; Croghan, Michael ; Jordan, Steve R.

On page 309, the third author's first name should be "Marian" instead of "Marion.".

2014-01-23·Journal of Medicinal Chemistry1区 · 医学

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

1区 · 医学

Article

作者: Norman, Mark H. ; Bartberger, Michael D. ; Tamayo, Nuria ; Tadesse, Seifu ; Lloyd, David J. ; Galbreath, Elizabeth ; Jordan, Steven R. ; Chen, Jie ; Helmering, Joan ; Cupples, Rod ; Zhang, Jiandong ; Chmait, Samer ; Hale, Clarence ; Liu, Longbin ; Poon, Steve F. ; St. Jean, David J. ; Nishimura, Nobuko ; Sivits, Glenn ; Van, Gwyneth ; Hong, Fang-Tsao ; Fotsch, Christopher ; Stec, Markian M. ; Pennington, Lewis D. ; Yang, Kevin C. ; Reid, Darren ; Kunz, Roxanne K. ; Michelsen, Klaus ; Ashton, Kate S.

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.

2014-01-23·Journal of Medicinal Chemistry1区 · 医学

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

1区 · 医学

Article

作者: Andrews, Kristin L. ; Hale, Clarence ; Fotsch, Christopher ; Zhang, Jiandong ; Michelsen, Klaus ; Cupples, Rod ; Helmering, Joan ; Poon, Steve F. ; Kurzeja, Robert J. M. ; Chen, Jie ; Wahl, Robert C. ; Sivits, Glenn ; Chen, Michelle ; Pennington, Lewis D. ; Chen, Kui ; Van, Gwyneth ; Ashton, Kate S. ; Lloyd, David J. ; Bryan, Marion C. ; Chmait, Samer ; Croghan, Michael ; Vonderfecht, Steve L. ; St. Jean, David J. ; Jordan, Steve R.

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.

100 项与 AMG-1694 相关的药物交易

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