title: N-(2-oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: synthesis and structure-activity and structure-property relationships.
abstract: The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC(50) = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Piazza del Rinascimento 6, I-61029 Urbino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonietti
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004952:Esters; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D011789:Quantum Theory; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C574769:2-methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester; D002219:Carbamates; D004952:Esters; D007783:Lactones; D012710:Serum Albumin, Bovine; D000581:Amidohydrolases