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121.
Meena K. Purohit Iain Scovell Anton Neschadim Yulia Katsman Donald R. Branch Lakshmi P. Kotra 《Bioorganic & medicinal chemistry letters》2013,23(8):2324-2327
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 IC50 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. 相似文献
122.
Shannon Atkinson Diane Gendron Trevor A. Branch Kendall L. Mashburn Valentina Melica Luis E. Enriquez-Paredes Robert L. Brownell Jr. 《Marine Mammal Science》2020,36(1):6-28
Hormonal biomarkers are useful indicators of mammalian reproductive and metabolic states. The present study validated and applied the use of progesterone and cortisol blubber assays for studies of blue whales from the Gulf of California, Mexico. In a validation study for pregnancy detection, blubber progesterone concentrations were correlated with pregnancy status for four female blue whales: three resighted with a calf the year following sampling and the fourth stranded with a fetus. The progesterone concentrations were significantly higher than those measured in juvenile whales (n = 3). In the application study, blubber samples from blue whales (51 noncalf females, 2 female calves, 48 noncalf males, and 1 male calf) with known sighting histories were analyzed. Putative pregnant females had elevated progesterone concentrations. Cortisol concentrations did not differ between male and female blue whales, or among females in different reproductive classes. After correcting for uncertain ages, hence maturity status, the pregnancy rate of noncalf females was 33.4% (95% CI 32.2%–34.3%). Although interpretation of hormone biomarkers must consider all physiological states that may influence progesterone concentrations, these results demonstrate the utility of pairing hormone biomarkers with sighting histories to help assess environmental or anthropogenic impacts on reproduction in blue whales. 相似文献
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