title: Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase.
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.
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Genin
authors.affiliation: 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.
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Gonzalez Valcarcel
authors.affiliation: 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.
authors.forename: William G
authors.initials: WG
authors.lastname: Holloway
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Lamar
authors.affiliation: 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.
authors.forename: Marian
authors.initials: M
authors.lastname: Mosior
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Hawkins
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Estridge
authors.affiliation: 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.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weidner
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seng
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Yurek
authors.affiliation: 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.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Adams
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weller
authors.affiliation: 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.
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Reynolds
authors.affiliation: 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.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; C000619660:imidazopyridine; C000619661:pyrazolopiperidine; D051102:Serine C-Palmitoyltransferase