title: Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF).
abstract: The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also exhibits keto-enol tautomerase activity, believed to be vestigial in mammals. Starting from a 1 μM hit from virtual screening, substituted benzoxazol-2-ones have been discovered as antagonists with IC(50) values as low as 7.5 nM in a tautomerase assay and 80 nM in a MIF-CD74 binding assay. Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts.
authors: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors: Alissa A
authors: AA
authors: Hare
authors: Lin
authors: L
authors: Leng
authors: Sunilkumar
authors: S
authors: Gandavadi
authors: Xin
authors: X
authors: Du
authors: Zoe
authors: Z
authors: Cournia
authors: Richard
authors: R
authors: Bucala
authors: William L
authors: WL
authors: Jorgensen
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D005347:Fibroblasts / Q000201:enzymology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D001583:Benzoxazoles; D000949:Histocompatibility Antigens Class II; D011971:Receptors, Immunologic; C045084:invariant chain; C033184:macrophage migration inhibitory factor receptor; C017057:benzoxazolone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3