2. Academic Validation
  3. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles

Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles

  • J Med Chem. 2014 Jan 23;57(2):325-38. doi: 10.1021/jm4016747.
David J St Jean Jr 1,  Kate S Ashton,  Michael D Bartberger,  Jie Chen,  Samer Chmait,  Rod Cupples,  Elizabeth Galbreath,  Joan Helmering,  Fang-Tsao Hong,  Steven R Jordan,  Longbin Liu,  Roxanne K Kunz,  Klaus Michelsen,  Nobuko Nishimura,  Lewis D Pennington,  Steve F Poon,  Darren Reid,  Glenn Sivits,  Markian M Stec,  Seifu Tadesse,  Nuria Tamayo,  Gwyneth Van,  Kevin C Yang,  Jiandong Zhang,  Mark H Norman,  Christopher Fotsch,  David J Lloyd,  Clarence Hale
Affiliations

Affiliation

  • 1 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.
PMID: 24405213 DOI: 10.1021/jm4016747
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.

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