ABSTRACT
The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl]-phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non-competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogs of SX-517 and SX-576, identifying (2-{(benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5-pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability.
Subject(s)
Boronic Acids/pharmacology , Niacinamide/analogs & derivatives , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Biological Availability , Boronic Acids/administration & dosage , Boronic Acids/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Niacinamide/administration & dosage , Niacinamide/chemistry , Niacinamide/pharmacology , Solubility , Structure-Activity Relationship , Water/chemistryABSTRACT
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.
Subject(s)
Boronic Acids/chemistry , Niacinamide/analogs & derivatives , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Boronic Acids/therapeutic use , Computational Biology , Drug Design , Inflammation/chemically induced , Inflammation/drug therapy , Lung Diseases/chemically induced , Lung Diseases/drug therapy , Molecular Structure , Niacinamide/chemistry , Niacinamide/therapeutic use , Ozone/toxicity , Rats , Rats, Sprague-Dawley , Receptors, Interleukin-8B/chemistryABSTRACT
The G protein-coupled chemokine receptors CXCR1 and CXCR2 play key roles in inflammatory diseases and carcinogenesis. In inflammation, they activate and recruit polymorphonuclear cells (PMNs) through binding of the chemokines CXCL1 (CXCR1) and CXCL8 (CXCR1 and CXCR2). Structure-activity studies that examined the effect of a novel series of S-substituted 6-mercapto-N-phenyl-nicotinamides on CXCL1-stimulated Ca(2+) flux in whole human PMNs led to the discovery of 2-[5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic acid (SX-517), a potent noncompetitive boronic acid CXCR1/2 antagonist. SX-517 inhibited CXCL1-induced Ca(2+) flux (IC50 = 38 nM) in human PMNs but had no effect on the Ca(2+) flux induced by C5a, fMLF, or PAF. In recombinant HEK293 cells that stably expressed CXCR2, SX-517 antagonized CXCL8-induced [(35)S]GTPγS binding (IC50 = 60 nM) and ERK1/2 phosphorylation. Inhibition was noncompetitive, with SX-517 unable to compete the binding of [(125)I]-CXCL8 to CXCR2 membranes. SX-517 (0.2 mg/kg iv) significantly inhibited inflammation in an in vivo murine model. SX-517 is the first reported boronic acid chemokine antagonist and represents a novel pharmacophore for CXCR1/2 antagonism.
Subject(s)
Boronic Acids/chemistry , Niacinamide/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding, Competitive , Boronic Acids/pharmacology , Chemokine CXCL1/antagonists & inhibitors , Combinatorial Chemistry Techniques , HEK293 Cells/drug effects , Humans , Inflammation/drug therapy , Interleukin-8/metabolism , MAP Kinase Signaling System/drug effects , Male , Mice, Inbred Strains , Neutrophils/drug effects , Niacinamide/chemistry , Phosphorylation , Receptors, Interleukin-8B/metabolism , Structure-Activity RelationshipABSTRACT
An acute decrease in cardiac performance can result from a reduced free triiodothyronine (FT3) level following (i) brain death (euthyroid sick syndrome), (ii) a period of cardiopulmonary bypass, and possibly (iii) regional or global myocardial ischemia. The two major pathophysiologic effects of brain death are (i) vascular injury associated with the hemodynamic consequences of the autonomic 'storm', and (ii) a generalized inhibition of mitochondrial function, which results in diminished organ function from the loss of energy stores from a rapid loss of circulating FT3. Deterioration of donor organ function can be reversed by hormonal replacement therapy, in which T3 plays a critical role. This results in (i) an increased number of organs being functionally acceptable, and (ii) increased early and intermediate graft survival. Cardiopulmonary bypass is associated with a reduction in the circulating level of FT3, and this can be associated with deterioration in cardiac function. The administration of T3 at the time of discontinuation of cardiopulmonary bypass reverses this state. In patients undergoing heart transplantation, T3 therapy to both donor and recipient is beneficial.
