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Bioorg Med Chem Lett. 2014 Feb 15;24(4):1144-7. doi: 10.1016/j.bmcl.2013.12.126. Epub 2014 Jan 8.

Undesired versus designed enzymatic cleavage of linkers for liver targeting.

Author information

1
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
2
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
3
Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
4
Pfizer Global Research & Development, 620 Memorial Drive, Cambridge, MA 02139, USA. Electronic address: robert.l.dow@pfizer.com.
5
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. Electronic address: mgfinn@gatech.edu.

Abstract

A design for the selective release of drug molecules in the liver was tested, involving the attachment of a representative active agent by an ester linkage to various 2-substituted 5-aminovaleric acid carbamates. The anticipated pathway of carboxylesterase-1-mediated carbamate cleavage followed by lactamization and drug release was frustrated by unexpectedly high sensitivity of the ester linkage toward hydrolysis by carboxylesterase-2 and other microsomal components.

KEYWORDS:

Carboxylesterase; Cleavable linkers; Drug targeting; Liver targeting

PMID:
24461291
PMCID:
PMC4319531
DOI:
10.1016/j.bmcl.2013.12.126
[Indexed for MEDLINE]
Free PMC Article

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