Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase

  • J Med Chem. 2016 Jun 23;59(12):5904-10. doi: 10.1021/acs.jmedchem.5b01851.
Michael J Genin  1 ,  Isabel C Gonzalez Valcarcel  1 ,  William G Holloway  1 ,  Jason Lamar  1 ,  Marian Mosior  1 ,  Eric Hawkins  1 ,  Thomas Estridge  1 ,  Jeffrey Weidner  1 ,  Thomas Seng  1 ,  David Yurek  1 ,  Lisa A Adams  1 ,  Jennifer Weller  1 ,  Vincent L Reynolds  1 ,  Joseph T Brozinick  1
Affiliations
  • 1. Discovery Chemistry Research and Technology, ‡Cardiovascular and Metabolic Diseases Therapeutic Area, §Diabetes Therapeutic Area, ∥Drug Disposition and Metabolism, ⊥Quantitative Biology, and #Non-Clinical Safety, Lilly Research Laboratories, a Division of Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
PMID: 27213958 DOI: 10.1021/acs.jmedchem.5b01851
Abstract

To develop novel treatments for Type 2 Diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma Ceramides in rodents, have a slight trend toward enhanced Insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in Cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.

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