title: Human Toll-like Receptor (TLR) 8-Specific Agonistic Activity in Substituted Pyrimidine-2,4-diamines.
abstract: Activation of human toll-like receptor-8 (TLR8) evokes a distinct cytokine profile favoring the generation of Type 1 helper T cells. A multiplexed high-throughput screen had led to the identification of N(4)-butyl-5-iodo-6-methylpyrimidine-2,4-diamine as a pure TLR8 agonist, and a detailed structure-activity relationship study of this chemotype was undertaken. A butyl substituent at N(4) was optimal, and replacement of the 5-iodo group with chloro, bromo, or fluoro groups led to losses in potency, as did the introduction of aromatic bulk. Drawing from our previous structure-based design, several 5-alkylamino derivatives were evaluated. Significant enhancement of potency was achieved in 5-(4-aminobutyl)-N(4)-butyl-6-methylpyrimidine-2,4-diamine. This compound potently induced Th1-biasing IFN-γ and IL-12 in human blood, but lower levels of the proinflammatory cytokines IL-1β, IL-6, and IL-8. These results suggest that the inflammatory and reactogenic propensities of this compound could be considerably more favorable than other TLR8 agonists under evaluation.
authors: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Mallesh
authors: M
authors: Beesu
authors: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Alex C D
authors: AC
authors: Salyer
authors: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Kathryn L
authors: KL
authors: Trautman
authors: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Justin K
authors: JK
authors: Hill
authors: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Sunil A
authors: SA
authors: David
mesh_terms: D018122:B7-1 Antigen / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D009000:Monocytes / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000235:genetics
chemical_list: D018122:B7-1 Antigen; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D011743:Pyrimidines; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D007371:Interferon-gamma