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
  • 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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