δ-thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors

Dana V. Ferraris; Pavel Majer; Chiyou Ni; C. Ethan Slusher; Rana Rais; Ying Wu; Krystyna M. Wozniak; Jesse Alt; Camilo Rojas; Barbara S. Slusher; Takashi Tsukamoto

doi:10.1021/jm401703a

δ-thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors

Dana V. Ferraris, Pavel Majer, Chiyou Ni, C. Ethan Slusher, Rana Rais, Ying Wu, Krystyna M. Wozniak, Jesse Alt, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

School of Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC ₅₀ for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.

Original language	English (US)
Pages (from-to)	243-247
Number of pages	5
Journal	Journal of medicinal chemistry
Volume	57
Issue number	1
DOIs	https://doi.org/10.1021/jm401703a
State	Published - Jan 9 2014

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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abstract = "δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC 50 for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.",

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AU - Ferraris, Dana V.

AU - Majer, Pavel

AU - Ni, Chiyou

AU - Slusher, C. Ethan

AU - Rais, Rana

AU - Wu, Ying

AU - Wozniak, Krystyna M.

AU - Alt, Jesse

AU - Rojas, Camilo

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

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Y1 - 2014/1/9

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δ-thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors

Abstract

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