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The S1P1 receptor is the target of four marketed drugs for the treatment of multiple sclerosis and ulcerative colitis. Targeting an S1P exporter, specifically Spns2, that is "upstream" of S1P receptor engagement is an alternate strategy that might recapitulate the efficacy of S1P receptor modulators without cardiac toxicity. We recently reported the first Spns2 inhibitor SLF1081851 (16d) that has modest potency with in vivo activity. To develop more potent compounds, we initiated a structure-activity relationship study that identified 2-aminobenzoxazole as a viable scaffold. Our studies revealed SLB1122168 (33p), which is a potent inhibitor (IC50 = 94 ± 6 nM) of Spns2-mediated S1P release. Administration of 33p to mice and rats resulted in a dose-dependent decrease in circulating lymphocytes, a pharmacodynamic indication of Spns2 inhibition. 33p provides a valuable tool compound to explore both the therapeutic potential of targeting Spns2 and the physiologic consequences of selective S1P export inhibition.

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A facile method to access (Z)-1,3-enynes is realized via sequential copper-catalyzed regio- and stereoselective borylation-protodeboronation of 1,3-diynes. Pinacolborane, copper(II) acetate, and Xantphos as the ligand efficiently install hydrogen and Bpin in a cis fashion, which is followed by rapid hydrolysis with water. The reaction has wide substrate scope and occurs in a chemoselective fashion.

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Small-molecule mitochondrial uncouplers are gaining recognition as potential therapeutics for metabolic diseases such as obesity, diabetes, and nonalcoholic steatohepatitis (NASH). Specifically, heterocycles derived from BAM15, a potent and mitochondria-selective uncoupler, have yielded promising preclinical candidates that are efficacious in animal models of obesity and NASH. In this study, we report the structure-activity relationship studies of 6-amino-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol derivatives. Using oxygen consumption rate as a readout of mitochondrial uncoupling, we established 5-hydroxyoxadiazolopyridines as mild uncouplers. In particular, SHM115, which contains a pentafluoro aniline, had an EC50 value of 17 µM and exhibited 75% oral bioavailability. SHM115 treatment increased the energy expenditure and lowered the body fat mass in two diet-induced obesity mouse models, including an obesity prevention model and an obesity reversal model. Taken together, our findings demonstrate the therapeutic potential of mild mitochondrial uncouplers for the prevention of diet-induced obesity.

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Early studies suggested that FeIII complexes cannot compete with GdIII complexes as T1 MRI contrast agents. Now it is shown that one member of a class of high-spin macrocyclic FeIII complexes produces more intense contrast in mice kidneys and liver at 30 minutes post-injection than does a commercially used GdIII agent and also produces similar T1 relaxivity in serum phantoms at 4.7 T and 37 °C. Comparison of four different FeIII macrocyclic complexes elucidates the factors that contribute to relaxivity in vivo including solution speciation. Variable-temperature 17 O NMR studies suggest that none of the complexes has a single, integral inner-sphere water that exchanges rapidly on the NMR timescale. MRI studies in mice show large in vivo differences of three of the FeIII complexes that correspond, in part, to their r1 relaxivity in phantoms. Changes in overall charge of the complex modulate contrast enhancement, especially of the kidneys.

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