2013
DOI: 10.1039/c3ob40816g
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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… Show more

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Cited by 39 publications
(57 citation statements)
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“…[8a, 13b, 19] A homologous series of compounds were also synthesized (Scheme S1). As in other chemotypes that we had previously explored, [8a, 13b, 19b, 20] and consistent with the dimensions of the binding pocket in TLR8, [16] we observed in this homologous series a clear dependence of substituent chain length at C3 with the optimal analogue being 6 , which showed maximal agonistic potency in a cell-based TLR8-specific NF-κB transactivation assay (EC 50 of 2.2 μM; Figs. 5, S3, Table 1).…”
supporting
confidence: 89%
“…[8a, 13b, 19] A homologous series of compounds were also synthesized (Scheme S1). As in other chemotypes that we had previously explored, [8a, 13b, 19b, 20] and consistent with the dimensions of the binding pocket in TLR8, [16] we observed in this homologous series a clear dependence of substituent chain length at C3 with the optimal analogue being 6 , which showed maximal agonistic potency in a cell-based TLR8-specific NF-κB transactivation assay (EC 50 of 2.2 μM; Figs. 5, S3, Table 1).…”
supporting
confidence: 89%
“…Imiquimod and R-848, but not CL264, share a chemical structure known as quinoline. This structure, not required for TLR7 agonism (39), is also present in other bronchodilatory compounds with undefined mechanisms of action, including the bitter taste receptor (TAS2R) agonists quinine and chloroquine. Quinine and chloroquine relax precontracted mouse, guinea pig, and human airways, at similar potencies to imiquimod (9,15,26,32) and have been shown to induce [Ca 2ϩ ] i mobilization (9), as well as inhibit subsequent calcium release by other agents (14,30,35).…”
Section: Discussionmentioning
confidence: 99%
“…29 We therefore synthesized all possible regioisomeric benzologues of 8b (Scheme 3). The naphtho[2,3- d ]imidazole analogue 13 was accessed readily via cyclization of the naphthalene-2,3-diamine with CNBr.…”
Section: Resultsmentioning
confidence: 99%
“…We next targeted all possible regioisomers of imidazopyridines ( 27a – d ) for possible TLR7/8 activity, given that these analogues are congeneric to the imidazo[4,5- c ] pyridines 29 (Scheme 4). These analogues were synthesized via S N Ar reactions of corresponding o -halonitropyridines with pentylamine, reduction of the nitro group, and final cyclization with CNBr (Scheme 4).…”
Section: Resultsmentioning
confidence: 99%
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