title: Structure-activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias.
abstract: Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N(1) positions of the bivalent pyrazole core to be important for the inhibitory activity.
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: Meena K
authors.initials: MK
authors.lastname: Purohit
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Sai Kumar
authors.initials: SK
authors.lastname: Chakka
authors.affiliation: Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Iain
authors.initials: I
authors.lastname: Scovell
authors.affiliation: Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Anton
authors.initials: A
authors.lastname: Neschadim
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Bello
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Noruê
authors.initials: N
authors.lastname: Salum
authors.affiliation: Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Katsman
authors.affiliation: Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Madeleine C
authors.initials: MC
authors.lastname: Bareau
authors.affiliation: Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Branch
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada; McLaughlin Center for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: lkotra@uhnres.utoronto.ca.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D000906:Antibodies / Q000276:immunology; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy / Q000276:immunology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000906:Antibodies; D011720:Pyrazoles; C031280:pyrazole
keywords: Immune thrombocytopenia; Phagocytosis inhibitors; Pyrazole derivatives; Structure–activity relationship