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Undesired versus designed enzymatic cleavage of linkers for liver targeting.
Chirapu, Srinivas R; Bauman, Jonathan N; Eng, Heather; Goosen, Theunis C; Strelevitz, Timothy J; Sinha, Subhash C; Dow, Robert L; Finn, M G.
Affiliation
  • Chirapu SR; Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
  • Bauman JN; Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
  • Eng H; Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
  • Goosen TC; Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
  • Strelevitz TJ; Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
  • Sinha SC; Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
  • Dow RL; Pfizer Global Research & Development, 620 Memorial Drive, Cambridge, MA 02139, USA. Electronic address: robert.l.dow@pfizer.com.
  • Finn MG; Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. Electronic address: mgfinn@gatech.edu.
Bioorg Med Chem Lett ; 24(4): 1144-7, 2014 Feb 15.
Article in En | MEDLINE | ID: mdl-24461291
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carbamates / Carboxylic Ester Hydrolases / Drug Design / Amino Acids, Neutral / Carboxylesterase / Liver Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2014 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carbamates / Carboxylic Ester Hydrolases / Drug Design / Amino Acids, Neutral / Carboxylesterase / Liver Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2014 Document type: Article Affiliation country: Estados Unidos