| Autor: |
Rowley JA, Reid RC, Poon EKY, Wu KC, Lim J, Lohman RJ, Hamidon JK, Yau MK, Halili MA, Durek T, Iyer A, Fairlie DP |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2020 Jan 23; Vol. 63 (2), pp. 529-541. Date of Electronic Publication: 2020 Jan 07. |
| DOI: |
10.1021/acs.jmedchem.9b00927 |
| Abstrakt: |
Structure-activity relationships for a series of small-molecule thiophenes resulted in potent and selective antagonism of human Complement C3a receptor. The compounds are about 100-fold more potent than the most reported antagonist SB290157. A new compound JR14a was among the most potent of the new antagonists in vitro, assessed by (a) inhibition of intracellular calcium release (IC 50 10 nM) induced in human monocyte-derived macrophages by 100 nM C3a, (b) inhibition of β-hexosaminidase secretion (IC 50 8 nM) from human LAD2 mast cells degranulated by 100 nM C3a, and (c) selectivity for human C3aR over C5aR. JR14a was metabolically stable in rat plasma and in rat liver microsomes and efficacious in rats when given orally to suppress rat paw inflammation, macrophage and mast cell activation, and histopathology induced by intraplantar paw administration of a C3aR agonist. Potent C3aR antagonists are now available for interrogating C3a receptor activation and suppressing C3aR-mediated inflammation in mammalian physiology and disease. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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