Design and Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potent Inhibitors of Phosphodiesterase4B2

Authors

  • Dalip Kumar,

    Corresponding author
    1. Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan 333 031, India
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  • Gautam Patel,

    1. Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan 333 031, India
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  • Lalitha Vijayakrishnan,

    1. Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D-III, Plot No 20 Sector 18, Gurgaon 122015, Haryana, India
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  • Sunanda G. Dastidar,

    1. Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D-III, Plot No 20 Sector 18, Gurgaon 122015, Haryana, India
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  • Abhijit Ray

    1. Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D-III, Plot No 20 Sector 18, Gurgaon 122015, Haryana, India
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Corresponding author: Dalip Kumar, dalipk@bits-pilani.ac.in

Abstract

A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50 = 5.28 μm). Structure–activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat.

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