Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model

Abstract

Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation.

The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry

“…In another study, SX-517 ( Table 5 ) was the first reported boronic acid chemokine antagonist for CXCR 1 and 2 and was able to significantly inhibit inflammation in vivo [ 126 ]. SX-517 was eventually replaced with a new lead compound SX-576 ( Table 5 ), which had greater systemic exposure, greater inhibition in vitro, increased metabolic stability, and improved pharmacokinetic properties in vivo [ 127 ]. Lastly, a structure-activity relationship (SAR) study was conducted to create an orally available compound with improved aqueous solubility with the same activity level as SX-576 [ 128 ].…”

Targeting chemokine receptors from the inside-out: discovery and development of small-molecule intracellular antagonists

“…During preclinical development of SX-517, problems arose related to its metabolic stability. 89 The compound was subject to oxidative cleavage of the boronic acid, transforming it into the inactive 2-hydroxybenzyl derivative. A focused SAR study to increase resistance to oxidative deborylation yielded compound SX-576 (37).…”

Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability

“…A focused SAR effort to increase metabolic stability led to the discovery of our second-generation inhibitor 6 (SX-576), which was less susceptible to oxidation of the boronic acid. 32 Modeling of the binding of 6 with CXCR2, constructed from the recently solved structure of CXCR1, 34 revealed that this class of antagonists has a different binding model than previously described for other classes of compounds. However, the poor aqueous solubility of 6 led us to examine whether heteroatom replacement of the sulfur could improve its oral bioavailability.…”

“…32,33 Our first-generation inhibitor 5 (SX-517) exhibited anti-inflammatory activity in vivo , but its preclinical development was halted due to its metabolic instability. A focused SAR effort to increase metabolic stability led to the discovery of our second-generation inhibitor 6 (SX-576), which was less susceptible to oxidation of the boronic acid.…”