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 journalArticlepeer-review

6 Scopus citations


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

Bibliographical note

Publisher Copyright:
Copyright © 2018 American Chemical Society.


  • ADAM10
  • animal studies
  • inhibitor
  • selectivity

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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