Discovery of potent inhibitors of human and mouse fatty acid amide hydrolases.
Fatty acid amide hydrolase (FAAH, EC 3.5.1.99) is the main enzyme catabolizing endocannabinoid fatty acid amides. FAAH inactivation promotes beneficial effects upon pain and anxiety without the side effects accompanying agonists of type-1 cannabinoid receptors. Aiming at discovering new selective FAAH inhibitors, we developed a series of compounds (5a-u) characterized by a functionalized heteroaromatic scaffold. Particularly, 5c and 5d were identified as extremely potent, noncompetitive, and reversible FAAH inhibitors endowed with a remarkable selectivity profile and lacking interaction with the hERG channels. In vivo antinociceptive activity was demonstrated for 5c, 5d, and 5n at a dose much lower than that able to induce either striatal and limbic stereotypies or anxiolytic activity, thus outlining their potential to turn into optimum preclinical candidates. Aiming at improving pharmacokinetic properties and metabolic stability of 5d, we developed a subset of nanomolar dialyzable FAAH inhibitors (5v-z), functionalized by specific polyethereal lateral chains and fluorinated aromatic rings.
European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
Stefania
S
Butini
Margherita
M
Brindisi
Sandra
S
Gemma
Patrizia
P
Minetti
Walter
W
Cabri
Grazia
G
Gallo
Silvia
S
Vincenti
Emanuela
E
Talamonti
Franco
F
Borsini
Antonio
A
Caprioli
Maria Antonietta
MA
Stasi
Stefano
S
Di Serio
Sindu
S
Ros
Giuseppe
G
Borrelli
Samuele
S
Maramai
Filomena
F
Fezza
Giuseppe
G
Campiani
Mauro
M
Maccarrone
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000201:enzymology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D017288:Pain Threshold; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D003510:Cyclohexanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005663:Furans; D011758:Pyrroles; D011994:Recombinant Proteins; D013876:Thiophenes; D000099252:Fatty Acid Amide Hydrolases; C000606913:KCNH2 protein, human