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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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
Volume9
Issue number7
DOIs
StatePublished - Jul 12 2018

Keywords

  • 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. https://doi.org/10.1021/acsmedchemlett.8b00163