RESUMEN
The most recently recognized types of immune cells, the innate lymphoid cells (ILCs), have been sub-divided according to respective distinct expression profiles of regulatory factors or/and cytokines. ILCs have also been shown to participate in a variety of beneficial immune responses, including participation in attack against pathogens and mediation of the pre-inflammatory and inflammatory responses through their production of pro-inflammatory cytokines. As such, while the ILCs exert protective effects they may also become detrimental upon dysregulation. Indeed, recent studies of the ILCs have revealed a strong association with the advent and pathogenesis of several common autoimmune diseases, including psoriasis, inflammatory bowel disease (IBD) and multiple sclerosis (MS). Though the ILCs belong to lineage negative cells that are distinctive from the Th cells, the profiles of secreted cytokines from the ILCs overlap with those of the corresponding Th subsets. Nevertheless, considering that the ILCs belong to the innate immune system and the Th cells belong to the adaptive immune system, it is expected that the ILCs should function at the early stage of diseases and the Th cells should exert predominant effects at the late stage of diseases. Therefore, it is intriguing to consider targeting of ILCs for therapy by targeting the corresponding cytokines at the early stage of diseases, with the late stage cytokine targeting mainly influencing the Th cells' function. Here, we review the knowledge to date on the roles of ILCs in various autoimmune diseases and discuss their potential as new therapeutic targets.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Citocinas/metabolismo , Inmunidad Innata , Inmunoterapia/métodos , Linfocitos/inmunología , Animales , Humanos , Células TH1/inmunología , Balance Th1 - Th2 , Células Th2/inmunologíaRESUMEN
A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC50 (FXa) value of 0.14µM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.
Asunto(s)
Anticoagulantes/síntesis química , Diseño de Fármacos , Inhibidores del Factor Xa/síntesis química , Factor Xa/química , Pirazoles/química , Piridinas/química , Animales , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Sitios de Unión , Coagulación Sanguínea/efectos de los fármacos , Dominio Catalítico , Factor Xa/metabolismo , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Pirazoles/farmacología , Pirazoles/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Conejos , Ratas , Relación Estructura-Actividad , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
Four series of novel and potent FXa inhibitors possessing the 1,2,4-triazole moiety and pyrrole moiety as P2 binding element and dihydroimidazole/tetrahydropyrimidine groups as P4 binding element were designed, synthesized, and evaluated for their anticoagulant activity in human and rabbit plasma in vitro. Most compounds showed moderate to excellent activity. Compounds 14a, 16, 18c, 26c, 35a, and 35b were further examined for their inhibition activity against human FXa in vitro and rat venous thrombosis in vivo. The most promising compound 14a, with an IC50 (FXa) value of 0.15µM and 99% inhibition rate, was identified for further evaluation as an FXa inhibitor.