In Search of Selectivity in Inhibition of ADAM10

Kiran V. Mahasenan, Derong Ding, Ming Gao, Trung T. Nguyen, Mark A. Suckow, Valerie A. Schroeder, William R. Wolter, Mayland Chang, Shahriar Mobashery

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The metalloproteinase ADAM10 has been reported as an important target for drug discovery in several human diseases. In this vein, (6S,7S)-N-hydroxy-5-methyl-6-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)-5-azaspiro[2.5]octane-7-carboxamide (compound 1) has been reported as a selective ADAM10 inhibitor. We synthesized this compound and document that it lacks both potency and selectivity in inhibition of ADAM10. This finding necessitated a structure-based computational analysis to investigate potency and selectivity of ADAM10 inhibition. The model that emerged indeed excluded compound 1 as an inhibitor for ADAM10, while suggesting another reported compound, (1R,3S,4S)-3-(hydroxycarbamoyl)-4-(4-phenylpiperidine-1-carbonyl)cyclohexyl pyrrolidine-1-carboxylate (compound 2), as an ADAM10 selective inhibitor. Compound 2 was synthesized and its potency, and selectivity in inhibition of ADAM10 were documented with a panel of several related enzymes. Pharmacokinetic studies of compound 2 in mice documented that the compound crosses the blood-brain barrier and may be useful as a pharmacological agent or mechanistic tool to delineate the role of ADAM10 in neurological diseases.

Original languageEnglish (US)
Pages (from-to)708-713
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number7
StatePublished - Jul 12 2018


  • ADAM10
  • animal studies
  • inhibitor
  • selectivity

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    Mahasenan, K. V., Ding, D., Gao, M., Nguyen, T. T., Suckow, M. A., Schroeder, V. A., Wolter, W. R., Chang, M., & Mobashery, S. (2018). In Search of Selectivity in Inhibition of ADAM10. ACS Medicinal Chemistry Letters, 9(7), 708-713.