title: Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication.
abstract: Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series, resulting in 10-fold improvement in potency in a WEEV replicon assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells, we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood-brain barrier. In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain.
authors.affiliation: Vahlteich Medicinal Chemistry Core and ‡Department of Medicinal Chemistry, College of Pharmacy, §Departments of Internal Medicine and Microbiology and Immunology, ∥Department of Neurology, ⊥Department of Neurosurgery, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Sindac
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Barraza
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Dobry
authors.forename: Jianming
authors.initials: J
authors.lastname: Xiang
authors.forename: Pennelope K
authors.initials: PK
authors.lastname: Blakely
authors.forename: David N
authors.initials: DN
authors.lastname: Irani
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D004667:Encephalitis Virus, Western Equine / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008970:Molecular Weight; D012995:Solubility; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000998:Antiviral Agents; D007211:Indoles