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dc.contributor.authorRowley, Jessica A
dc.contributor.authorReid, Robert C
dc.contributor.authorPoon, Eunice KY
dc.contributor.authorWu, Kai-Chen
dc.contributor.authorLim, Junxian
dc.contributor.authorLohman, Rink-Jan
dc.contributor.authorHamidon, Johan K
dc.contributor.authorYau, Mei-Kwan
dc.contributor.authorHalili, Maria A
dc.contributor.authorDurek, Thomas
dc.contributor.authorIyer, Abishek
dc.contributor.authorFairlie, David P
dc.date.accessioned2020-06-25T00:13:49Z
dc.date.available2020-06-25T00:13:49Z
dc.date.issued2020
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/acs.jmedchem.9b00927
dc.identifier.urihttp://hdl.handle.net/10072/394864
dc.description.abstractStructure-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 (IC50 10 nM) induced in human monocyte-derived macrophages by 100 nM C3a, (b) inhibition of β-hexosaminidase secretion (IC50 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.relation.ispartofpagefrom529
dc.relation.ispartofpageto541
dc.relation.ispartofissue2
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume63
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.titlePotent Thiophene Antagonists of Human Complement C3a Receptor with Anti-Inflammatory Activity
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationRowley, JA; Reid, RC; Poon, EKY; Wu, KC; Lim, J; Lohman, RJ; Hamidon, JK; Yau, MK; Halili, MA; Durek, T; Iyer, A; Fairlie, DP, Potent Thiophene Antagonists of Human Complement C3a Receptor with Anti-Inflammatory Activity, Journal of Medicinal Chemistry, 2020, 63 (2), pp. 529-541
dc.date.updated2020-06-25T00:06:39Z
gro.hasfulltextNo Full Text
gro.griffith.authorHalili, Maria A.


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