Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors

Alessio Moriconi; Chiara Bigogno; Gianluca Bianchini; Antonio Caligiuri; Anna Resconi; Massimo G Dondio; Gaetano D'Anniballe; Marcello Allegretti

doi:10.1021/ml2001533

Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors

ACS Med Chem Lett. 2011 Aug 7;2(10):768-73. doi: 10.1021/ml2001533. eCollection 2011 Oct 13.

Authors

Alessio Moriconi¹, Chiara Bigogno², Gianluca Bianchini¹, Antonio Caligiuri², Anna Resconi², Massimo G Dondio², Gaetano D'Anniballe¹, Marcello Allegretti¹

Affiliations

¹ Research Center, Dompé s.p.a., via Campo di Pile, 67100 L'Aquila, Italy.
² DMPK and Developability Department, Nikem Research Srl Via Zambeletti 25, 20021 Baranzate, Milan, Italy.

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.

Keywords: Aryltriflate; CXCR1; CXCR2; chemokine; drug profiling; dual noncompetitive inhibitor.