Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: modulation at the N-portion and distal phenyl ring

Giorgio Ortar; Enrico Morera; Luciano De Petrocellis; Alessia Ligresti; Aniello Schiano Moriello; Ludovica Morera; Marianna Nalli; Rino Ragno; Adele Pirolli; Vincenzo Di Marzo

doi:10.1016/j.ejmech.2013.02.005

Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: modulation at the N-portion and distal phenyl ring

Eur J Med Chem. 2013 May:63:118-32. doi: 10.1016/j.ejmech.2013.02.005. Epub 2013 Feb 15.

Authors

Giorgio Ortar¹, Enrico Morera, Luciano De Petrocellis, Alessia Ligresti, Aniello Schiano Moriello, Ludovica Morera, Marianna Nalli, Rino Ragno, Adele Pirolli, Vincenzo Di Marzo

Affiliation

¹ Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy. giorgio.ortar@uniroma1.it

PMID: 23474898
DOI: 10.1016/j.ejmech.2013.02.005

Abstract

In the present study, we have further extended the structure-activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0-9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH-MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1-32 did not display a unique pattern. The ability of tetrazoles 1-32 to act as TRPV1 and TRPA1 modulators was also investigated.

MeSH terms

Amidohydrolases / antagonists & inhibitors
Amidohydrolases / chemistry
Amidohydrolases / metabolism
Animals
COS Cells
Calcium Channels / metabolism
Chlorocebus aethiops
Dose-Response Relationship, Drug
Endocannabinoids / antagonists & inhibitors*
Endocannabinoids / metabolism*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
HEK293 Cells
Humans
Ion Channel Gating / drug effects
Models, Molecular
Molecular Structure
Monoacylglycerol Lipases / antagonists & inhibitors
Monoacylglycerol Lipases / chemistry
Monoacylglycerol Lipases / metabolism
Nerve Tissue Proteins / metabolism
Protein Binding
Protein Structure, Tertiary
Rats
Structure-Activity Relationship
TRPA1 Cation Channel
TRPV Cation Channels / metabolism
Tetrazoles / chemistry*
Tetrazoles / pharmacology*
Transient Receptor Potential Channels / metabolism
Urea / chemistry
Urea / pharmacology

Substances

Calcium Channels
Endocannabinoids
Enzyme Inhibitors
Nerve Tissue Proteins
TRPA1 Cation Channel
TRPA1 protein, human
TRPV Cation Channels
TRPV1 protein, human
Tetrazoles
Transient Receptor Potential Channels
Urea
Monoacylglycerol Lipases
Amidohydrolases
fatty-acid amide hydrolase