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Inhibition of the sodium-proton exchanger (NHE) plays an important role in reducing tissue damage during ischemic reperfusion injury; however, pharmacological inhibitors of NHE have restricted access to acutely ischemic tissues because of severely compromised tissue perfusion. We describe the syntheses, characterization, and NHE inhibitory activities of a novel class of amiloride derivatives where peptides are conjugated to the amiloride C(5) amino group. These new peptide-C(5)-amiloride conjugates are inactive; however, peptide residues were chosen such that selective cleavage by neutral endopeptidase 24.11 (enkephalinase) liberates an amino acid-C(5)-amiloride conjugate that inhibits NHE in a glial cell line. These results confirm the feasibility of using peptide-amiloride conjugates as NHE inhibitor prodrugs. We envision the design of analogous peptide-amiloride prodrugs that can be administered prior to ischemic events and subsequently activated by endopeptidases selectively expressed by ischemic tissues.

Inhibition of the sodium-proton exchanger (NHE) plays an important role in reducing tissue damage during ischemic reperfusion injury; however, pharmacological inhibitors of NHE have restricted access to acutely ischemic tissues because of severely compromised tissue perfusion. We describe the syntheses, characterization, and NHE inhibitory activities of a novel class of amiloride derivatives where peptides are conjugated to the amiloride C(5) amino group. These new peptide-C(5)-amiloride conjugates are inactive; however, peptide residues were chosen such that selective cleavage by neutral endopeptidase 24.11 (enkephalinase) liberates an amino acid-C(5)-amiloride conjugate that inhibits NHE in a glial cell line. These results confirm the feasibility of using peptide-amiloride conjugates as NHE inhibitor prodrugs. We envision the design of analogous peptide-amiloride prodrugs that can be administered prior to ischemic events and subsequently activated by endopeptidases selectively expressed by ischemic tissues.

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d-Glucal is converted to epoxy allylic alcohol 4using an eight-step sequence that features a stereoselective methyl Grignard addition to an iodo-hexenulose. Epoxide formation via intramolecular iodide displacement occurs subsequent to an unusual hemiacetal reduction protocol involving LiBH4in n-octanol. Alcohol 4and the corresponding aldehyde (Z)-14are potential C(4)–C(9) templates for eleutheside syntheses.

The flavonoid genistein and the benzo[c]quinolizinium MPB-07 have been shown to activate the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is defective in cystic fibrosis. Lead-based combinatorial and parallel synthesis yielded 223 flavonoid, quinolizinium, and related heterocyclic compounds. The compounds were screened for their ability to activate CFTR at 50 μmconcentration by measurement of the kinetics of iodide influx in Fisher rat thyroid cells expressing wild-type or G551D CFTR together with the green fluorescent protein-based halide indicator YFP-H148Q. Duplicate screenings revealed that 204 compounds did not significantly affect CFTR function. Compounds of the 7,8-benzoflavone class, which are structurally intermediate between flavones and benzo[c]quinoliziniums, were effective CFTR activators with the most potent being 2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate (UCcf-029). Compounds of the novel structural class of fused pyrazolo heterocycles were also strong CFTR activators with the most potent being 3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde (UCcf-180). A CFTR inhibitor was also identified. The active compounds did not induce iodide influx in null cells deficient in CFTR. Short-circuit current measurements showed that the CFTR activators identified by screening induced strong anion currents in the transfected cell monolayers grown on porous supports. Compared with genistein, the most active compounds had up to 10 times greater potency in activating wild-type and/or G551D-CFTR. The activators had low cellular toxicity and did not elevate cellular cAMP concentration or inhibit phosphatase activity, suggesting that CFTR activation may involve a direct interaction. These results establish an efficient screening procedure to identify CFTR activators and inhibitors and have identified 7,8-benzoflavones and pyrazolo derivatives as novel classes of CFTR activators.

3,3-Bis(3-fluorophenyl)-1-propanamine hydrochloride (NPS 846·HCl, 1a) is representative of a new class of diphenylpropylamine NMDA receptor antagonists. The corresponding radiolabelled ligand was prepared by catalytic tritiation of its precursor olefin (4), which was synthesized in a three-step reaction sequence starting from 3,3'-difluorobenzophenone (2). Catalytic tritiation of 4 was performed in a two-component solvent system ([3:1] 1,4-dioxane/methanol). The percentage of isotope incorporation was found to be dependent on the nature of the reaction solvent. Experiments with deuterium gas indicate that higher radiochemical incorporation can be obtained by reduction in either neat 1,4-dioxane or methyl alcohol-d. © 1998 John Wiley & Sons, Ltd.

3,3‐Bis(3‐fluorophenyl)‐1‐propanamine hydrochloride (NPS 846·HCl, 1a) is representative of a new class of diphenylpropylamine NMDA receptor antagonists. The corresponding radiolabelled ligand was prepared by catalytic tritiation of its precursor olefin (4), which was synthesized in a three‐step reaction sequence starting from 3,3′‐difluorobenzophenone (2). Catalytic tritiation of 4was performed in a two‐component solvent system ([3:1] 1,4‐dioxane/methanol). The percentage of isotope incorporation was found to be dependent on the nature of the reaction solvent. Experiments with deuterium gas indicate that higher radiochemical incorporation can be obtained by reduction in either neat 1,4‐dioxane or methyl alcohol‐d. © 1998 John Wiley & Sons, Ltd.