Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes

Pagire, Suvarna H.; Pagire, Haushabhau S.; Lee, Gwi Bin; Han, Seo‐Jung; Kwak, Hyun Jung; Kim, Ji Young; Kim, Ki Young; Rhee, Sang Dal; Ryu, Jeong Yong; Song, Jin Sook; Bae, Myung Ae; Park, Mijin; Kim, Dooseop; Lee, Duck‐Hyung; Ahn, Jin Hee

doi:10.1016/j.ejmech.2015.06.043

Cited by 9 publications

(1 citation statement)

References 22 publications

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“…In another application, AD has been conjugated to chemotherapeutic agents to maximize their therapeutic efficacy while minimizing their hepatic and cardiotoxicities [12,13,14]. Non-steroidal anti-inflammatory drugs (NSAIDs) and diacylglycerol acyltransferase 1 inhibitors (DGAT1) have also utilized AD modifications to increase the potency of NSAIDs and to create a novel DGAT1 inhibitor drug for more effective diabetic treatment [15,16]. Generally, when AD is conjugated to drugs, it functions to increase the drug’s hydrophobicity which can enable the drug to bind to tissue more readily.…”

Section: Introductionmentioning

confidence: 99%

Erythromycin Modification That Improves Its Acidic Stability while Optimizing It for Local Drug Delivery

et al. 2017

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The antibiotic erythromycin has limited efficacy and bioavailability due to its instability and conversion under acidic conditions via an intramolecular dehydration reaction. To improve the stability of erythromycin, several analogs have been developed—such as azithromycin and clarithromycin—which decrease the rate of intramolecular dehydration. We set out to build upon this prior work by developing a conjugate of erythromycin with improved pH stability, bioavailability, and preferential release from a drug delivery system directly at the low pH of an infection site. To develop this new drug conjugate, adamantane-1-carbohydrazide was covalently attached to erythromycin via a pH-degradable hydrazone bond. Since Staphylococcus aureus infection sites are slightly acidic, the hydrazone bond will undergo hydrolysis liberating erythromycin directly at the infection site. The adamantane group provides interaction with the drug delivery system. This local delivery strategy has the potential of reducing off-target and systemic side-effects. This work demonstrates the synthesis of a pH-cleavable, erythromycin conjugate that retains the inherent antimicrobial activity of erythromycin, has an increased hydrophobicity, and improved stability in acidic conditions; thereby enhancing erythromycin’s bioavailability while simultaneously reducing its toxicity.

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