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Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.

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Four tachykinin (NK2) receptor inhibitors, SCH 378161 (1), SCH 217048 (2), SCH 378199 (3), and SCH 378167 (4) were isolated from the fermentation broth of a taxonomically unidentified fungus. These compounds were separated from the fermentation broth by ethyl acetate extraction. Purification and separation of the individual compoundswere achieved by NK2assay-guided fractionation using gel filtration, reverse phase chromatography and HPLC. They were identified to be a family of depsipeptides by spectroscopic and degradation studies. Compounds1 and 3 contain proline and differ as an amide and acid whereas 2 and 4 contain pipecolic acid and differ in being an amide and acid. All of these compoundscontain an identical hydroxy acid. They are selective NK2 inhibitors with Ki values ranging from 27-982nM and demonstrate no activity at IO^m in the NKj and NK3assays. In addition, compounds 1 and 2 inhibited NKA-induced increases in the concentration of intracellular Ca2+, [Ca2+]j, in a CHOcell expressing the human NK2 receptor; this inhibition was competitive in nature with pA2 values of 7.2 and 7.5, respectively. These data demonstrate that these natural products are selective and competitive receptor antagonists of the humanNK2receptor.