title: Synthesis and Characterization of Fatty Acid Conjugates of Niacin and Salicylic Acid.
abstract: This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Bemis
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Ericka
authors.initials: E
authors.lastname: Benson
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bista
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Carney
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Fahrner
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Diana
authors.initials: D
authors.lastname: Lee
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Lonkar
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Milne
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nichols
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Dominic
authors.initials: D
authors.lastname: Picarella
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Shoelson
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Smith
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Amal
authors.initials: A
authors.lastname: Ting
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Wensley
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Maisy
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Zimmer
authors.affiliation: Catabasis Pharmaceuticals , One Kendall Square, Suite B14202, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020156:Salicylic Acid / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005227:Fatty Acids; D016328:NF-kappa B; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D009525:Niacin; D020156:Salicylic Acid