title: Disulfide linked pyrazole derivatives inhibit phagocytosis of opsonized blood cells.
abstract: Immune thrombocytopenia (ITP) is caused by production of an autoantibody to autologous platelets. ITP can be treated either by reducing platelet destruction or by increasing platelet production. Fcγ receptor mediated phagocytosis of the opsonized blood cells is a well-accepted mechanism for the underlying pathogenesis of ITP and inhibition of this phagocytosis process with small molecules is a potential strategy for the development of drugs against ITP. A broad screen indicated that 4-methyl-1-phenyl-pyrazole derivative (1) could inhibit the phagocytosis of opsonized blood cells with weak potency. We reveal here the discovery of the polysulfide products, synthesis of various 1-phenyl-pyrazole derivatives, and the biological evaluation of pyrazole derivatives as inhibitors of phagocytosis for potential use as therapeutics for ITP. Substitution at C4 of the pyrazole moiety in the disulfide-bridged dimers influenced the potency in the increasing order of 10 ~/= 11~/= 16 < 19 < 20. A novel scaffold, 20 with an IC(50) of 100 nM inhibiting opsonized blood cell phagocytosis was identified as a potential candidate for further studies. Confirmation of the disulfide bridge additionally provides clues for the non-thiol or non-disulfide bridge carrying ligands targeting ITP and other similar disorders.
authors.affiliation: Center for Molecular Design and Preformulations, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Meena K
authors.initials: MK
authors.lastname: Purohit
authors.forename: Iain
authors.initials: I
authors.lastname: Scovell
authors.forename: Anton
authors.initials: A
authors.lastname: Neschadim
authors.forename: Yulia
authors.initials: Y
authors.lastname: Katsman
authors.forename: Donald R
authors.initials: DR
authors.lastname: Branch
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood* / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004220:Disulfides; D011720:Pyrazoles