title: Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties.
abstract: A straightforward synthesis of pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones was developed starting from 2-chloropyridine-3-carboxylic acid by esterification, nucleophilic aromatic substitution and amide formation in one step, and ring closure allowing their synthesis with two identical or two different group attached to nitrogen. The structural diversity of these [2,3-d]pyrimidine-2,4(1H,3H)-diones resulted in significant variation in the biopharmaceutical properties. This was reflected by the broad range in fasted state simulated intestinal fluid solubility values (12.6 μM to 13.8 mM), Caco-2 permeability coefficients (1.2 × 10(-6)cm/s to 90.7 × 10(-6)cm/s) and in vitro-predicted human in vivo intrinsic clearance values (0 to 159 ml/min/kg).
authors.affiliation: Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
authors.forename: Martyna
authors.initials: M
authors.lastname: Jatczak
authors.affiliation: Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Muylaert
authors.affiliation: Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
authors.forename: Laurens M
authors.initials: LM
authors.lastname: De Coen
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Pharmaceutical Sciences, KU Leuven, O&N II Herestraat 49-box 921, 3000 Leuven, Belgium.
authors.forename: Janneke
authors.initials: J
authors.lastname: Keemink
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Pharmaceutical Sciences, KU Leuven, O&N II Herestraat 49-box 921, 3000 Leuven, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wuyts
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Pharmaceutical Sciences, KU Leuven, O&N II Herestraat 49-box 921, 3000 Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: chris.stevens@ugent.be.
authors.forename: Christian V
authors.initials: CV
authors.lastname: Stevens
mesh_terms: D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000737:chemistry; D002463:Cell Membrane Permeability / Q000187:drug effects; D004951:Esterification; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D002264:Carboxylic Acids; D011744:Pyrimidinones
keywords: ADME; Pyridopyrimidines; Pyrimidinediones; Pyrimidines