RESUMEN
The discovery of a series of phenylalanine derived CCR3 antagonists is reported. Parallel, solution-phase library synthesis has been utilized to delineate the structure-activity relationship leading to the synthesis of highly potent, CCR3-selective antagonists.
Asunto(s)
Fenilalanina/química , Fenilalanina/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Humanos , Receptores CCR3 , Receptores de Quimiocina/metabolismo , Relación Estructura-ActividadRESUMEN
Highly potent CCR3 antagonists have been developed from a previously reported series of phenylalanine ester-based leads. Solution-phase, parallel synthesis optimization was utilized to identify highly potent, functional CCR3 antagonists.
Asunto(s)
Fenilalanina/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Humanos , Fenilalanina/síntesis química , Fenilalanina/química , Receptores CCR3 , Receptores de Quimiocina/metabolismo , Relación Estructura-ActividadRESUMEN
A versatile synthetic route to a novel series of bis-imidazolemethanes designed to inhibit the hCMV protease has been developed and a series of potential metal binding inhibitors has been identified. In selectivity assays, the compounds were highly specific for CMV protease and showed no inhibition (IC50 > 100 microM) of other prototypical serine proteases such as trypsin, elastase, and chymotrypsin. Although the presence of free zinc ions was found to be an absolute requirement for the in vitro biological activity of this class of inhibitor, the potency of the inhibitors could not be improved beyond the micromolar level.
Asunto(s)
Imidazoles/síntesis química , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/síntesis química , Quimotripsina/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Imidazoles/química , Metales , Conformación Molecular , Estructura Molecular , Elastasa Pancreática/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Tripsina/metabolismoRESUMEN
Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating peptides acting through CC chemokine receptor-3 (CCR3). Thus, antagonism of CCR3 could have a therapeutic role in asthma and other eosinophil-mediated diseases. A high throughput, cellular functional screen was configured using RBL-2H3 cells stably expressing CCR3 (RBL-2H3-CCR3) to identify non-peptide receptor antagonists. A small molecule CCR3 antagonist was identified, SK&F 45523, and chemical optimization led to the generation of a number of highly potent, selective CCR3 antagonists including SB-297006 and SB-328437. These compounds were further characterized in vitro and demonstrated high affinity, competitive inhibition of (125)I-eotaxin and (125)I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca(2+) mobilization in RBL-2H3-CCR3 cells and eosinophils. Additionally, SB-328437 inhibited eosinophil chemotaxis induced by three ligands that activate CCR3 with similar potencies. Selectivity was affirmed using a panel of 10 seven-transmembrane receptors. This is the first description of a non-peptide CCR3 antagonist, which should be useful in further elucidating the pathophysiological role of CCR3 in allergic inflammatory diseases.
Asunto(s)
Benzamidas/farmacología , Movimiento Celular/efectos de los fármacos , Quimiocinas CC/antagonistas & inhibidores , Citocinas/antagonistas & inhibidores , Eosinófilos/efectos de los fármacos , Proteínas Quimioatrayentes de Monocitos/antagonistas & inhibidores , Naftalenos/farmacología , Fenilalanina/análogos & derivados , Receptores de Quimiocina/antagonistas & inhibidores , Receptores del VIH/antagonistas & inhibidores , Asma/fisiopatología , Unión Competitiva , Calcio/metabolismo , Línea Celular , Quimiocina CCL11 , Quimiocina CCL24 , Humanos , Fenilalanina/farmacología , Receptores CCR3 , Receptores de Quimiocina/fisiologíaRESUMEN
A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki=40+/-3 nM, kobs/[I]=6. 6x10(5) M-1.s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0+/-0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki=6.3+/-0.5 microM, kobs/[I]=1.6x10(4) M-1.s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine.
Asunto(s)
Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , Lipoproteínas LDL/metabolismo , Fosfolipasas A/metabolismo , Sulfóxidos/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Arildialquilfosfatasa , Quimiotaxis de Leucocito/efectos de los fármacos , Esterasas/antagonistas & inhibidores , Humanos , Oxidación-Reducción , Fosfatidilcolina-Esterol O-Aciltransferasa/antagonistas & inhibidores , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A2 , Unión ProteicaRESUMEN
A novel class of CMV protease inhibitors based on a benzothiopyran-S,S-dioxide nucleus has been discovered. Enzyme kinetic data supports a reversible mode of inhibition for a representative member of this class, 2-(3-pyridyl-N-oxide)benzothiopyran-4-one-S,S-dioxide, 1. Experiments in the presence and absence of the disulfide reducing agent DTT suggest that the inhibition by 1 is not due to oxidative inactivation of the enzyme. Also presented are results of some SAR studies of the benzothiopyranone ring system.
Asunto(s)
Pironas/farmacología , Serina Endopeptidasas/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacología , Secuencia de Aminoácidos , Citomegalovirus/enzimología , Datos de Secuencia Molecular , Oxidación-Reducción , Pironas/química , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
The synthesis and phosphodiesterase (PDE) inhibitory profile of a series of imidazopyridines, including sulmazole and isomazole, on separated PDE isoenzymes are described. The results show that both sulmazole and isomazole are weak inhibitors of PDE III, and their inotropic activity is unlikely to be due to PDE III inhibition alone. Surprisingly, both compounds were found to be significant inhibitors of the cGMP specific isoenzyme, PDE V, and a series of simple 2-substituted phenylimidazo[4,5-b]pyridines have been made to investigate the SAR of PDE activity. This has been shown to be sensitive to chain length, polarity, and the nature of the heteroatom linking group. Potent PDE V inhibitors, many of which are also significant inhibitors of PDE IV, have been identified.