title: Discovery of phosphoric acid mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} ester (Lu AA47070): a phosphonooxymethylene prodrug of a potent and selective hA(2A) receptor antagonist.
abstract: The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.
authors.affiliation: Medicinal Chemistry Research, Lundbeck Research Denmark, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen Valby, Denmark. anette.sams@leo-pharma.com
authors.forename: Anette G
authors.initials: AG
authors.lastname: Sams
authors.forename: Gitte K
authors.initials: GK
authors.lastname: Mikkelsen
authors.forename: Mogens
authors.initials: M
authors.lastname: Larsen
authors.forename: Morten
authors.initials: M
authors.lastname: Langgård
authors.forename: Mark E
authors.initials: ME
authors.lastname: Howells
authors.forename: Tenna J
authors.initials: TJ
authors.lastname: Schrøder
authors.forename: Lise T
authors.initials: LT
authors.lastname: Brennum
authors.forename: Lars
authors.initials: L
authors.lastname: Torup
authors.forename: Erling B
authors.initials: EB
authors.lastname: Jørgensen
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgård
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010755:Organophosphates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014867:Water
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D010755:Organophosphates; D011355:Prodrugs; D013844:Thiazoles; C559609:phosphoric acid mono-(2-(4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino)thiazol-3-ylmethyl) ester; D014867:Water