James J. Folmer

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Caspase-3 is an intracellular cysteine protease, activated as part of the apoptotic response to cell injury. Its interest as a therapeutic target has led many to pursue the development of inhibitors. To date, only one series of nonpeptidic inhibitors have been described, and these have limited selectivity within the caspase family. Here we report the(More)
Studies on the biotransformation of isoxazole rings have shown that molecules containing a C3-substituted isoxazole or a 1,2-benzisoxazole can undergo a two-electron reductive ring cleavage to form an imine. In the absence of a C3 substituent, the isoxazole ring opens via deprotonation of the C3 proton followed by N-O bond cleavage to yield an α-cyanoenol(More)
A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originated from trans-4-hydroxy-L-proline (10), which was converted(More)
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary(More)
ed at higher pH and form the enol form M1 (Scheme 6). The mass spectra of the molecular ion of M3 at m/z 633 suggest formation of a GSH-adduct. The formation of the second generation product ions at m/z 202 and 160 from the ion at m/z 326 suggests the 2-isopropyl-5,7-dimethylisoindolin-1-one moiety is intact. Studies with C-labeled methanol resulted in a 1(More)
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; μ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as(More)
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