Discovery of anthranilamides as a novel class of inhibitors of neurotropic alphavirus replication.
Neurotropic alphaviruses are debilitating pathogens that infect the central nervous system (CNS) and are transmitted to humans via mosquitoes. There exist no effective human vaccines against these viruses, underlining the need for effective antivirals, but no antiviral drugs are available for treating infection once the viruses have invaded the CNS. Previously, we reported the development of novel indole-2-carboxamide-based inhibitors of alphavirus replication that demonstrate significant reduction of viral titer and achieve measurable brain permeation in a pharmacokinetic mouse model. Herein we report our continued efforts to improve physicochemical properties predictive of in vivo blood-brain barrier (BBB) permeability through reduction of overall molecular weight, replacing the indole core with a variety of aromatic and non-aromatic monocyclics. These studies culminated in the identification of simple anthranilamides that retain excellent potency with improved metabolic stability and significantly greater aqueous solubility. Furthermore, in a live virus study, we showed that two new compounds were capable of reducing viral titer by two orders of magnitude and that these compounds likely exert their effects through a mechanism similar to that of our indole-2-carboxamide inhibitors.
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States.
Scott J
SJ
Barraza
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
Philip C
PC
Delekta
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States.
Janice A
JA
Sindac
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
Craig J
CJ
Dobry
Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States.
Jianming
J
Xiang
Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States.
Richard F
RF
Keep
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: milldavi@umich.edu.
David J
DJ
Miller
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: sdlarsen@med.umich.edu.
Scott D
SD
Larsen
D000524:Alphavirus / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
D000998:Antiviral Agents; D062367:ortho-Aminobenzoates; C000219:anthranilamide
Drug development; Medicinal chemistry; Virology