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These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (Hepatology 2016;64:1430-1441).

We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.

Leukotriene B4 is a potent activator for polymorphonuclear (PMN) 1eukocytes.l It causes increased chemotactic and chemokinetic migration, aggregation, degranulation, lysosomal enzymes release, and free radical release. Because of these biological activities, LTB4 may play an important role in inflammatory diseases in which elevated levels of LTB4 have been detected, such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. The effects Of LTB4 are mediated through high-and low-affinity receptors on the surface of leukocytes. Since many receptor antagonists of other potent mediators have already demonstrated therapeutic value in man, the search for LTB4 receptor antagonists represents a rational therapeutic approach to inflammatory diseases. In this communication, we report the discovery of a potent new LTB4 antagonist.Several LTB4 receptor antagonists with a variety of biological activities have been reported in the literature. For example, SC-41930 (11, a well-studied LTB4 antagonist with multiple biological activities, exhibits only moderate binding affinity (ICs0 = 300 nM) to human neutrophils.2 Upjohn reported a series of LTB4 structure-based antagonists with ICs0 values ranging from 80 to 400 nM, but most of the compounds appear to exhibit mixed agonist/ antagonist a~tivity.~ Recently, Eli Lilly has reported LY 223982 (2) as a potent LTB4 antagonist with an ICs0 of 12 nM against human PMN LTB4 receptor^.^ ONO-LB-457 (3), which has a similar but slightly modified structure, is (1) For a recent review and relevent references, see: Kingsbury, W.; Daines, R.; Gleason, J.

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