RESUMEN
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Asunto(s)
Química Farmacéutica/métodos , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/química , Administración Oral , Animales , Quimiotaxis , Perros , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Modelos Químicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series.
Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Animales , Humanos , Estructura Molecular , Piperidinas/química , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Delta32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
Asunto(s)
Antagonistas de los Receptores CCR5 , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón/inmunología , Macrófagos/inmunología , Pirazoles/administración & dosificación , Linfocitos T/inmunología , Tolerancia al Trasplante/efectos de los fármacos , Valina/análogos & derivados , Animales , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Autoinmunidad/efectos de los fármacos , Autoinmunidad/inmunología , Ciclosporina/administración & dosificación , Modelos Animales de Enfermedad , Supervivencia de Injerto/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Trasplante de Corazón/patología , Humanos , Inmunosupresores/administración & dosificación , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Isoanticuerpos/inmunología , Trasplante de Riñón/inmunología , Macaca fascicularis , Macrófagos/patología , Masculino , Estrés Fisiológico/tratamiento farmacológico , Estrés Fisiológico/inmunología , Estrés Fisiológico/patología , Linfocitos T/patología , Tolerancia al Trasplante/inmunología , Trasplante Homólogo , Valina/administración & dosificación , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/inmunología , Enfermedades Vasculares/patologíaRESUMEN
A series of low molecular weight antagonists of both the human and murine CC chemokine receptor 2, containing a 1-alkyl-3-(3-methyl-4-spiroindenylpiperidine)-substituted cyclopentanecarboxamide, is described. A SAR study of the C(1) substituent revealed that short, branched alkyl groups such as isopropyl, isobutyl, or cyclopropyl are optimal for both human and murine CCR2 binding activity.
Asunto(s)
Amidas/química , Amidas/síntesis química , Carbono/química , Química Farmacéutica/métodos , Ciclopentanos/química , Ciclopentanos/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Quimiocina/metabolismo , Animales , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Leucocitos/metabolismo , Masculino , Ratones , Peso Molecular , Ratas , Ratas Sprague-Dawley , Receptores CCR2 , Relación Estructura-ActividadRESUMEN
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).
Asunto(s)
Amidas/síntesis química , Ciclopentanos/síntesis química , Piperidinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Ciclopentanos/química , Ciclopentanos/farmacología , Humanos , Técnicas In Vitro , Ratones , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Piperidinas/química , Piperidinas/farmacología , Receptores CCR2 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have identified and synthesized a series of diaryl substituted pyrazoles as potent antagonists of the chemokine receptor subtype 2. Structure-activity relationship studies directed toward improving the potency led to the discovery of 23 (IC50 = 6 nM).
Asunto(s)
Pirazoles/síntesis química , Pirazoles/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Quimiotaxis/efectos de los fármacos , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Monocitos/efectos de los fármacos , Oxidación-Reducción , Receptores CCR2 , Receptores de Quimiocina/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
Asunto(s)
Glicina/análogos & derivados , Monocitos/efectos de los fármacos , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Sitios de Unión , Células CHO/efectos de los fármacos , Calcio/metabolismo , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/metabolismo , Cricetinae , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Biológicos , Receptores CCR2 , Receptores de Quimiocina/metabolismoRESUMEN
OBJECTIVE: Leukotriene B4 (LTB4), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB4 are not well understood. This study is to determine candidate mechanisms. METHOD AND RESULTS: Primary human monocytes were treated with LTB4 and the supernatant was analyzed for cytokine/chemokine production by an immuno-protein array. This analysis revealed a strong increase of the monocyte chemoattractant protein-1 (MCP-1), a proinflammatory cytokine. Follow-up analyses with MCP-1 enzyme-linked immunosorbent assay (for quantitation of MCP-1 protein) and real-time polymerase chain reaction (PCR) (for MCP-1 mRNA) demonstrated that LTB4 strongly induced expression of MCP-1 protein and mRNA in a time-dependent and dose-dependent fashion. This induction was effectively abolished by CP-105,696, an antagonist for the LTB4 receptor BLT1. Selective inhibitors of ERK1/2 or JNK MAPK effectively blocked the LTB4-induced MCP-1 production. Furthermore, LTB4 increased NF-[kappa]B DNA binding activity, which was blocked by CP-105,696. CONCLUSIONS: LTB4 strongly induces MCP-1 production in primary human monocytes. This induction is mediated through the BLT1 pathway increasing MCP-1 transcription. Activation of ERK1/2 or JNK MAPK is essential for this induction. The NF-[kappa]B activation may be involved in LTB4-increased MCP-1 expression. The LTB4-induced MCP-1 in human monocytes may play a critical role in the atherogenicity of LTB4.