TY - JOUR
T1 - In Search of Selectivity in Inhibition of ADAM10
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 - Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/7/12
Y1 - 2018/7/12
N2 - 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.
AB - 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.
KW - ADAM10
KW - animal studies
KW - inhibitor
KW - selectivity
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U2 - 10.1021/acsmedchemlett.8b00163
DO - 10.1021/acsmedchemlett.8b00163
M3 - Article
AN - SCOPUS:85048713875
VL - 9
SP - 708
EP - 713
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 7
ER -
