Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues.

Article Details

Citation

Copy to clipboard

Shukla NM, Malladi SS, Mutz CA, Balakrishna R, David SA

Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues.

J Med Chem. 2010 Jun 10;53(11):4450-65. doi: 10.1021/jm100358c.

PubMed ID

20481492 [ View in PubMed

]

Abstract

Engagement of toll-like receptors serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. A structure-activity study was conducted on the TLR7-agonistic imidazoquinolines, starting with 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan- 2-ol as a lead. Modifications of the secondary amine of the C2 ethylaminomethylene side chain are poorly tolerated. The 4-amino group must be retained for activity. Replacement of the imidazole ring of the scaffold with triazole or cyclic urea led to complete loss of activity. A systematic exploration of N(1)-benzyl-C2-alkyl substituents showed a very distinct relationship between alkyl length and TLR7-agonistic potency with the optimal compound bearing a C2-n-butyl group. Transposition of the N(1) and C2 substituents led to the identification of an extremely active TLR7-agonistic compound with an EC(50) value of 8.6 nM. The relative potencies in human TLR7-based primary reporter gene assays were paralleled by interferon-alpha induction activities in whole human blood models.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Imiquimod	Toll-like receptor 7	EC 50 (nM)	2120	N/A	N/A	Details