Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 14, Pages 4142-4148Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900274q
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Funding
- National Graduate School of Organic Chemistry and Chemical Biology
- Academy of Finland [108569, 214334]
- Farmos the Diabetes Research Funding Foundation
- Emil Aaltonen Foundation
- Alfred Kordelin Foundation
- Finnish Konkordia Foundation
- Jenny and Antti Wihuri Foundation
- Academy of Finland (AKA) [108569, 214334, 108569, 214334] Funding Source: Academy of Finland (AKA)
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Metformin is a potent antidiabetic agent and currently used as a first-line treatment for patients with type 2 diabetes. Unfortunately, the moderate absorption and uncomfortable gastrointestinal adverse effects associated with metformin therapy impair its use. In this study, two novel prodrugs of a biguanidine functionality containing antidiabetic agent, metformin, were designed, synthesized, and evaluated in vitro and in vivo to accomplish improved lipophilicity and, consequently, enhanced oral absorption of this highly water-soluble drug. These results represent that the more lipophilic prodrug 2a biotransformed quantitatively to metformin mainly after absorption. The enhanced oral absorption consequently promoted the bioavailability of metformin from 43% to 65% in rats. Thus, this novel prodrug may offer a solution to reduce the required daily doses of metformin. which may decrease the uncomfortable adverse effects associated with metformin therapy.
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