Bone-targeting glycol and NSAIDS ester prodrugs of rhein: synthesis, hydroxyapatite affinity, stability, anti-inflammatory, ulcerogenicity index and pharmacokinetics studies.
Although rhein and NSAIDs are potent anti-inflammatory drugs, their use has been limited by the high incidence of gastrointestinal erosions and the necessity to deliver the drug to specific sites of target organ. Using the prodrug approach, a series of rhein-NSAIDs prodrugs containing anthraquinone bone-targeting moiety were synthesized by linking rhein with NSAIDs through glycol ester. The target compounds demonstrated significant capability of binding to HAP and were hydrolytically activated in physiological conditions. Hybrid rhein-NSAIDs prodrugs exhibited significant anti-inflammatory activity, moreover, the tested compounds were also found to possess less degree of ulcerogenic potential. Our pharmacokinetic studies of 7e demonstrated this prodrug is a potential candidate for a slower and sustained release form of rhein.
School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
Jin
J
Cai
Yanbing
Y
Duan
Jia
J
Yu
Junqing
J
Chen
Meng
M
Chao
Min
M
Ji
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D017886:Durapatite / Q000378:metabolism*; D004952:Esters; D005260:Female; D006018:Glycols / Q000737:chemistry*; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D014456:Ulcer / Q000139:chemically induced*
D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D006018:Glycols; D011355:Prodrugs; D017886:Durapatite; C020491:rhein