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Design, synthesis and structure–activity relationship of new HSL inhibitors guided by pharmacophore models

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Abstract

Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores. Its inhibition may improve insulin sensitivity and blood glucose handling in type 2 diabetes. Accordingly, many small-molecule HSL inhibitors have recently been identified. In continuation of our efforts for discovery of new HSL inhibitors, we prepared a variety of esters, amides, sulfonamides and sulfonate esters capable of fitting two pharmacophore models that we developed and published earlier. The tested compounds were synthesized via coupling reactions of aroyl chlorides or sulfonyl chlorides with phenols, amines and related derivatives. Our efforts led to the identification of interesting compounds of low micromolar anti-HSL bioactivities, which have potential to be developed into effective antidiabetic agents.

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Acknowledgments

This project was partially sponsored by the Faculty of Graduate Studies (M.Sc. Thesis of Jumana Dawood). The authors thank the Deanship of Scientific research University of Jordan and Hamdi Mango Centre for their financial supports.

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Correspondence to Mutasem O. Taha.

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Al-Shawabkeh, J.D., Al-Nadaf, A.H., Dahabiyeh, L.A. et al. Design, synthesis and structure–activity relationship of new HSL inhibitors guided by pharmacophore models. Med Chem Res 23, 127–145 (2014). https://doi.org/10.1007/s00044-013-0616-2

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