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

doi:10.1021/acsmedchemlett.8b00163

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 journal › Article › peer-review

3 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 language	English
Pages (from-to)	708-713
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00163
State	Published - Jul 12 2018

Bibliographical note

Funding Information:
This work was supported by a grant from the Craig H. Neilsen Foundation. Notes The authors declare no competing financial interest.

Publisher Copyright:
Copyright © 2018 American Chemical Society.

Keywords

ADAM10
animal studies
inhibitor
selectivity

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsmedchemlett.8b00163

Cite this

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title = "In Search of Selectivity in Inhibition of ADAM10",

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.",

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

note = "Funding Information: This work was supported by a grant from the Craig H. Neilsen Foundation. Notes The authors declare no competing financial interest. Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society.",

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doi = "10.1021/acsmedchemlett.8b00163",

language = "English",

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AU - Mahasenan, Kiran V.

AU - Ding, Derong

AU - Gao, Ming

AU - Nguyen, Trung T.

AU - Suckow, Mark A.

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Chang, Mayland

AU - Mobashery, Shahriar

N1 - Funding Information: This work was supported by a grant from the Craig H. Neilsen Foundation. Notes The authors declare no competing financial interest. Publisher Copyright: Copyright © 2018 American Chemical Society.

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In Search of Selectivity in Inhibition of ADAM10

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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