title: Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibitors.
abstract: Dipyridamole (Persantine) is a clinically used vasodilator with equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2) inhibitory activity albeit less potent than the prototype ENT1 inhibitor nitrobenzylmercaptopurine riboside (NBMPR). Dipyridamole is a good candidate for further exploration because it is a non-nucleoside and has a proven record of safe use in humans. A series of dipyridamole analogues were synthesized with systematic modification and evaluated as ENT1 inhibitors by flow cytometry. Compounds with much higher potency were identified, the best being 2,6-bis(diethanolamino)-4,8-diheptamethyleneiminopyrimido[5,4-d]pyrimidine (13) with a K(i) of 0.49 nM compared to a K(i) of 308 nM for dipyridamole. Compound 13 is similar in potency to the prototype potent ENT1 inhibitor NBMPR (0.43 nM). For the first time, a dipyridamole analogue has been identified that is equipotent with NBMPR. The SAR indicated that diethanolamine substituted analogues were more active than monoethanolamine compounds. Also, free hydroxyl groups are not essential for activity.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, 847 Monroe Avenue, Suite 327, Memphis, TN 38163, USA.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
mesh_terms: D045744:Cell Line, Tumor; D004176:Dipyridamole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C524111:2,6-bis(diethanolamino)-4,8-diheptamethyleneiminopyrimido(5,4-d)pyrimidine; D033721:Equilibrative Nucleoside Transporter 1; D006573:Heterocyclic Compounds, 1-Ring; D011743:Pyrimidines; D004176:Dipyridamole