title: Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors.
abstract: Interleukin-8 and growth related oncogene-α-chemokines (formerly CXCL8 and CXCL1, respectively) mediate chemotaxis of neutrophils to inflammatory sites via interactions with two transmembrane receptors, the type A CXCL8 receptor (CXCR1) and the type B CXCL8 receptor (CXCR2). In a previous work, we published the molecular modeling-driven structure activity relationship (SAR) results culminated in the discovery of R-(-)-2-[(4'-trifluoromethanesulphonyloxy)phenyl]-N-methanesulfonyl propionamide (19), in which an unusual aryltriflate moiety was embedded. Although triflates are broadly used in organic synthesis, this group is scarcely used in medicinal chemistry programs. Here we detail the drug profiling-driven approach used for the selection and characterization of 19, the most potent dual CXCR1 and CXCR2 noncompetitive inhibitor described to date. Reported data suggest that the aryltriflate moiety might represent a valid choice for the selection of clinical candidates with suitable druglike properties.
authors.affiliation: Research Center, Dompé s.p.a., via Campo di Pile, 67100 L'Aquila, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Moriconi
authors.affiliation: DMPK and Developability Department, Nikem Research Srl Via Zambeletti 25, 20021 Baranzate, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.affiliation: Research Center, Dompé s.p.a., via Campo di Pile, 67100 L'Aquila, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bianchini
authors.affiliation: DMPK and Developability Department, Nikem Research Srl Via Zambeletti 25, 20021 Baranzate, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Caligiuri
authors.affiliation: DMPK and Developability Department, Nikem Research Srl Via Zambeletti 25, 20021 Baranzate, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Resconi
authors.affiliation: DMPK and Developability Department, Nikem Research Srl Via Zambeletti 25, 20021 Baranzate, Milan, Italy.
authors.forename: Massimo G
authors.initials: MG
authors.lastname: Dondio
authors.affiliation: Research Center, Dompé s.p.a., via Campo di Pile, 67100 L'Aquila, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: D'Anniballe
authors.affiliation: Research Center, Dompé s.p.a., via Campo di Pile, 67100 L'Aquila, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
keywords: Aryltriflate; CXCR1; CXCR2; chemokine; drug profiling; dual noncompetitive inhibitor