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J Med Chem. 2014 Jan 23;57(2):325-38. doi: 10.1021/jm4016747. Epub 2014 Jan 9.

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

Author information

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.

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.

PMID:
24405213
DOI:
10.1021/jm4016747
[Indexed for MEDLINE]

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