title: Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis.
abstract: Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Sindac
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Yestrepsky
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Barraza
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Bolduc
authors.forename: Pennelope K
authors.initials: PK
authors.lastname: Blakely
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.forename: David N
authors.initials: DN
authors.lastname: Irani
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
mesh_terms: D000208:Acute Disease; D000524:Alphavirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018354:Alphavirus Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D018792:Encephalitis, Viral / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008567:Membranes, Artificial; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012093:Replicon / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056189:Viral Tropism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C574653:1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)-N-(1-phenylethyl)piperidine-4-carboxamide; D000998:Antiviral Agents; D007211:Indoles; D008567:Membranes, Artificial; D010880:Piperidines; D011758:Pyrroles; D013876:Thiophenes