title: Structure-activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines.
abstract: Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of IFN-α/β which plays essential functions in the control of adaptive immunity. We had previously examined structure-activity relationships (SAR) in TLR7/8-agonistic imidazoquinolines with a focus on substituents at the N(1), C(2), N(3) and N(4) positions, and we now report SAR on 1H-imidazo[4,5-c]pyridines. 1-Benzyl-2-butyl-1H-imidazo[4,5-c]pyridin-4-amine was found to be a pure TLR7-agonist with negligible activity on TLR8. Increase in potency was observed in N(6)-substituted analogues, especially in those compounds with electron-rich substituents. Direct aryl-aryl connections at C6 abrogated activity, but TLR7 agonism was reinstated in 6-benzyl and 6-phenethyl analogues. Consistent with the pure TLR7-agonistic behavior, prominent IFN-α induction in human PBMCs was observed with minimal proinflammatory cytokine induction. A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine. Distinct differences in N(6)-substituted analogues were observed with respect to IFN-α induction in human PBMCs on the one hand, and CD69 upregulation in lymphocytic subsets, on the other.
authors: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047, USA. sdavid@ku.edu.
authors: Euna
authors: E
authors: Yoo
authors: Breanna M
authors: BM
authors: Crall
authors: Rajalakshmi
authors: R
authors: Balakrishna
authors: Subbalakshmi S
authors: SS
authors: Malladi
authors: Lauren M
authors: LM
authors: Fox
authors: Alec R
authors: AR
authors: Hermanson
authors: Sunil A
authors: SA
authors: David
mesh_terms: D016207:Cytokines / Q000032:analysis; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007118:Immunoassay; D016898:Interferon-alpha / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics
chemical_list: D016207:Cytokines; D007093:Imidazoles; D016898:Interferon-alpha; D011725:Pyridines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7