Unique Polypharmacology Nuclear Receptor Modulator Blocks Inflammatory Signaling Pathways.
ACS Chem Biol
; 14(5): 1051-1062, 2019 05 17.
Article
en En
| MEDLINE
| ID: mdl-30951276
ABSTRACT
Obesity and rheumatic disease are mechanistically linked via chronic inflammation. The orphan receptor TREM-1 (triggering receptor expressed on myeloid cells-1) is a potent amplifier of proinflammatory and noninfectious immune responses. Here, we show that the pan modulator SR1903 effectively blocks TREM-1 activation. SR1903 emerged from a chemical series of potent RORγ inverse agonists, although unlike close structural analogues, it has modest agonist activity on LXR and weak repressive activity (inverse agonism) of PPARγ, three receptors that play essential roles in inflammation and metabolism. The anti-inflammatory and antidiabetic efficacy of this unique modulator in collagen-induced arthritis and diet-induced obesity mouse models is demonstrated. Interestingly, in the context of obesity, SR1903 aided in the maintenance of the thymic homeostasis unlike selective RORγ inverse agonists. SR1903 was well-tolerated following chronic administration, and combined, these data suggest that it may represent a viable strategy for treatment of both metabolic and inflammatory disease. More importantly, the ability of SR1903 to block LPS signaling suggests the potential utility of this unique polypharmacological modulator for treatment of innate immune response disorders.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Compuestos de Bifenilo
/
Receptores Citoplasmáticos y Nucleares
/
Propanoles
/
Polifarmacología
/
Inflamación
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
ACS Chem Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos