Undesired versus designed enzymatic cleavage of linkers for liver targeting

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Chirapu, Srinivas R.¹  Bauman, Jonathan N.³  Eng, Heather³  Goosen, Theunis C.³  Strelevitz, Timothy J.³  Sinha, Subhash C.²  Dow, Robert L.⁴  Finn, M. G.¹ 

[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA

[3] Pfizer Global Res & Dev, Groton, CT 06340 USA

[4] Pfizer Global Res & Dev, Cambridge, MA 02139 USA

关键词: Cleavable linkers;    Drug targeting;    Liver targeting;    Carboxylesterase;   

DOI  :  10.1016/j.bmcl.2013.12.126

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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