title: Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: modulation at the N-portion and distal phenyl ring.
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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy. giorgio.ortar@uniroma1.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ortar
authors.forename: Enrico
authors.initials: E
authors.lastname: Morera
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.forename: Ludovica
authors.initials: L
authors.lastname: Morera
authors.forename: Marianna
authors.initials: M
authors.lastname: Nalli
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Adele
authors.initials: A
authors.lastname: Pirolli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D015220:Calcium Channels / Q000378:metabolism; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry* / Q000494:pharmacology*; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D014508:Urea / Q000737:chemistry / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D015220:Calcium Channels; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; D013777:Tetrazoles; D050051:Transient Receptor Potential Channels; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C473350:TRPA1 protein, human; C494482:TRPV1 protein, human