title: N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists.
abstract: Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
authors.affiliation: IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Danila
authors.initials: D
authors.lastname: Branca
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dessole
authors.forename: Alberto
authors.initials: A
authors.lastname: Bresciani
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fonsi
authors.forename: Claudio
authors.initials: C
authors.lastname: Giuliano
authors.forename: Laura
authors.initials: L
authors.lastname: Llauger Bufi
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Palumbi
authors.forename: Caterina
authors.initials: C
authors.lastname: Torrisi
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D000072086:Smoothened Receptor; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; C498555:Smo protein, rat; D000072086:Smoothened Receptor