title: Discovery of a highly potent series of TLR7 agonists.
abstract: The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
authors: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. peter.jones2@pfizer.com
authors: Peter
authors: P
authors: Jones
authors: David C
authors: DC
authors: Pryde
authors: Thien-Duc
authors: TD
authors: Tran
authors: Fiona M
authors: FM
authors: Adam
authors: Gerwyn
authors: G
authors: Bish
authors: Frederick
authors: F
authors: Calo
authors: Guiseppe
authors: G
authors: Ciaramella
authors: Rachel
authors: R
authors: Dixon
authors: Jonathan
authors: J
authors: Duckworth
authors: David N A
authors: DN
authors: Fox
authors: Duncan A
authors: DA
authors: Hay
authors: James
authors: J
authors: Hitchin
authors: Nigel
authors: N
authors: Horscroft
authors: Martin
authors: M
authors: Howard
authors: Carl
authors: C
authors: Laxton
authors: Tanya
authors: T
authors: Parkinson
authors: Gemma
authors: G
authors: Parsons
authors: Katie
authors: K
authors: Proctor
authors: Mya C
authors: MC
authors: Smith
authors: Nicholas
authors: N
authors: Smith
authors: Amy
authors: A
authors: Thomas
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007275:Injections, Intravenous; D007369:Interferon Inducers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007372:Interferons / Q000819:agonists*; D008862:Microsomes, Liver / Q000378:metabolism; D058990:Molecular Targeted Therapy; D008970:Molecular Weight; D011687:Purines / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000998:Antiviral Agents; D007369:Interferon Inducers; D011687:Purines; D051199:Toll-Like Receptor 7; D007372:Interferons; D042931:Aldehyde Oxidase