期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 50, 期 16, 页码 3906-3920出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm070311l
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资金
- NCI NIH HHS [CA 101856, R03 CA105327-01A1, R15 CA101856-01, R15 CA101856, R03 CA105327, R03 CA105327-02, CA 105327] Funding Source: Medline
- NIAID NIH HHS [R21 AI065372-01, R21 AI065372-02, AI 065372, R21 AI065372] Funding Source: Medline
Dipyridamole (Persantine) is a clinically used vasodilator with equilibrative nucleoside transporters I 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-diheptamethylene-iminopyrimido[5,4-d]pyrimidine (13) with a K-i of 0.49 nM compared to a Ki 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.
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