Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2

Abstract

Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.

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

“…13 In agreement with previously published SAR and coherently with the proposed binding mode, different functionalizations of the phenylpropionyl scaffold, including aromatic/aliphatic amides, hydroxamates, and ABSTRACT: Interleukin-8 and growth related oncogeneÀR-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 modelingdriven structure activity relationship (SAR) results culminated in the discovery of R-(À)-2-[(4 0 -trifluoromethanesulphonyloxy) phenyl]-N-methanesulfonyl propionamide (19), in which an unusual aryltriflate moiety was embedded.…”

“…In an earlier paper, SAR results of potent CXCR1/CXCR2 noncompetitive inhibitors were disclosed. 13 As the main outcome of the work, aryltriflates showed a long plasma half-life in the tested species and dual activity to CXCR1 and CXCR2. Aryltriflates are excellent substrates for Stille and Suzuki cross-coupling reactions, Heck reactions, and BuchwaldÀHartwig reactions and are used as intermediates in medicinal chemistry programs due to the wide availability of structurally diverse phenols.…”

“…13 The paucity of medicinal chemistry data prompted us to be careful to consider the potential usefulness of this group; thus, the identified molecules were profiled along a screening cascade to ensure suitable developability potential. We assume that presumption of the biological liability of this moiety discouraged medicinal chemists from further investigation due to the possible in vivo formation of potentially toxic phenol derivatives and trifluoromethanesulfonic acid; thus, metabolic stability was carefully examined.…”

“…The synthesis of compounds 1À22 (Table 1) is reported in the Supporting Information while the biological activity was assessed as previously described. 13 The methodology used to prioritize the choice of preclinical candidates was the assembly of a specific screening grid defined for each chemical class. Table 1) was the first compound selected with an optimal biological activity profile.…”

“…13 The 2-aminopyridine derivative 3 was the a % inhibition ( SD (n = 3) on the CXCL8-induced human polymorphonucleate (PMN) chemotaxis at 10 À8 M. b % inhibition ( SD (n = 3) on the CXCL1-induced human PMN chemotaxis at 10 À8 M. c NA not active. less potent in this series, and unfortunately, substitutions around the pyridine ring were poorly tolerated (data not shown).…”