Synthesis and Metabolic Studies of Host Directed Inhibitors for Anti Viral Therapy

Terry W Moore; Kasinath Sana; Dan Yan; Stefanie A Krumm; Pahk Thepchatri; James P Snyder; José Marengo; Richard F Arrendale; Andrew J Prussia; Michael G Natchus; Dennis C Liotta; Richard K Plemper; Aiming Sun

doi:10.1021/ml400166b

Synthesis and Metabolic Studies of Host Directed Inhibitors for Anti Viral Therapy

ACS Med Chem Lett. 2013 Aug 8;4(8):762-767. doi: 10.1021/ml400166b.

Authors

Terry W Moore¹, Kasinath Sana, Dan Yan, Stefanie A Krumm, Pahk Thepchatri, James P Snyder, José Marengo, Richard F Arrendale, Andrew J Prussia, Michael G Natchus, Dennis C Liotta, Richard K Plemper, Aiming Sun

Affiliation

¹ Emory Institute for Drug Development, Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd., NE Atlanta, GA 30329, USA.

Abstract

Targeting host cell factors required for virus replication provides an alternative to targeting pathogen components and represents a promising approach to develop broad-spectrum antiviral therapeutics. High-throughput screening (HTS) identified two classes of inhibitors (2 and 3) with broad-spectrum antiviral activity against ortho- and paramyxoviruses including influenza A virus (IAV), measles virus (MeV), respiratory syncytial virus (RSV), and human parainfluenza virus type 3 (HPIV3). Hit-to-lead optimization delivered inhibitor, 28a, with EC₅₀ values of 0.88 and 0.81 μM against IAV strain WSN and MeV strain Edmonston, respectively. It was also found that compound 28a delivers good stability in human liver S9 fractions with a half-life of 165 minutes. These data establish 28a as a promising lead for antiviral therapy through a host-directed mechanism.

Keywords: Myxovirus inhibitor; benzimidazole; host-directed; influenza A; metabolic stability; respiratory syncytial virus.

Abstract

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