Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 15; pp. 3947 - 3956
• Main Authors: Jatczak, Martyna, Muylaert, Koen, De Coen, Laurens M., Keemink, Janneke, Wuyts, Benjamin, Augustijns, Patrick, Stevens, Christian V.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2014; Elsevier
• Subjects: ADME; Biochemistry & Molecular Biology; Caco-2 Cells; Carboxylic Acids - chemistry; Cell Membrane Permeability - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Esterification; Half-Life; Humans; Life Sciences & Biomedicine; Microsomes, Liver - metabolism; Pharmacology & Pharmacy; Physical Sciences; Pyridopyrimidines; Pyrimidinediones; Pyrimidines; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Science & Technology; Solubility; Pyridopyrimidines; Pyrimidines; ADME; Pyrimidinediones; TRANSFORMATION; DESIGN; PYRIDINE; BEHAVIOR; INHIBITORS; INTESTINAL FLUIDS; BINDING; SOLUBILITY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.06.009

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 (12.6μM to 13.8mM), Caco-2 permeability coefficients (1.2×10−6cm/s to 90.7×10−6cm/s) and in vitro-predicted human in vivo intrinsic clearance values (0 to 159ml/min/kg).