Structure-Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

J. Matthew Meinig, Skylar J. Ferrara, Tapasree Banerji, Tania Banerji, Hannah S. Sanford-Crane, Dennis Bourdette, Thomas (Tom) Scanlan

Research output: Contribution to journalArticle

Abstract

Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N-methyl (4), N-ethyl (5), N-fluoroethyl (15), and N-cyclopropyl (18) substantially favor selective CNS distribution of the parent drug in mice. Additionally, lead compounds exhibit moderate to good rates of hydrolysis at FAAH in vitro suggesting both enzymatic and physicochemical properties are important parameters for optimization. Both 4 and 15 were orally bioavailable while retaining appreciable CNS parent drug delivery following an oral dose. The pharmacokinetic parameters of 4 over 24 h postdose (i.v. and p.o.) were determined.

Original languageEnglish (US)
JournalACS Medicinal Chemistry Letters
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Prodrugs
Neurology
Structure-Activity Relationship
Central Nervous System
Thyroid Hormones
Amides
Hydrolysis
Central Nervous System Agents
Lead compounds
Demyelinating Diseases
Pharmacokinetics
Pharmaceutical Preparations
Drug delivery
fatty-acid amide hydrolase

Keywords

  • CNS
  • FAAH
  • Prodrug
  • remyelination
  • sobetirome
  • thyroid hormone

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Structure-Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs. / Meinig, J. Matthew; Ferrara, Skylar J.; Banerji, Tapasree; Banerji, Tania; Sanford-Crane, Hannah S.; Bourdette, Dennis; Scanlan, Thomas (Tom).

In: ACS Medicinal Chemistry Letters, 01.01.2018.

Research output: Contribution to journalArticle

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