Inhibition of Nucleoside Transport by New Analogues of 4-Nitrobenzylthioinosine:  Replacement of the Ribose Moiety by Substituted Benzyl Groups

• Published in: Journal of medicinal chemistry 2004-10, Vol.47 (22), p.5441-5450
• Main Authors: Tromp, Reynier A, van Ameijde, Susan, Pütz, Claudia, Sundermann, Corinna, Sundermann, Bernd, von Frijtag Drabbe Künzel, Jacobien K, IJzerman, Adriaan P
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Biological Transport - drug effects; Crystallography, X-Ray; Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors; Equilibrative Nucleoside Transporter 1 - chemistry; Erythrocyte Membrane - metabolism; Humans; In Vitro Techniques; Medical sciences; Miscellaneous; Models, Molecular; Nitrobenzenes - chemical synthesis; Nitrobenzenes - chemistry; Nitrobenzenes - pharmacology; Pharmacology. Drug treatments; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Radioligand Assay; Structure-Activity Relationship; Thionucleotides - chemical synthesis; Thionucleotides - chemistry; Thionucleotides - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049735v

4-Nitrobenzylthioinosine (NBTI, 1) is a well-known inhibitor for the nucleoside transport protein ENT1. However, its highly polar nature is unfavorable for oral absorption and/or penetration into the CNS. In the search for compounds with lower polarity than NBTI we replaced its ribose moiety by substituted benzyl groups. Halogen, hydroxyl, (trifluoro)methyl(-oxy), nitro, and amine functionalities were among the substituents at the benzyl group. In general, substitution of the benzyl group resulted in a lower affinity for ENT1. Only 2-hydroxyl substitution showed a higher affinity. Most likely this is the result of hydrogen bonding. Substitution at the 2-position of the benzyl group with aryl groups was also addressed. Compared to parent compound carrying a 2-phenylbenzyl group, all synthesized analogues gave higher affinities. Introduction of fluoro, trifluoromethyl, methoxy, and hydroxyl groups at the phenyl group clearly showed that addition to the 4-position was preferable. Despite the highly different character of a ribose and a benzyl group, K i values in the low nanomolar range were obtained for the benzyl-substituted derivatives. Compound 35, LUF5919, and compound 60, LUF5929, displayed the highest affinity (K i = 39 nM for both compounds), having a polar surface area of 101 Å2 and 85 Å2, respectively.