Undesired versus designed enzymatic cleavage of linkers for liver targeting.
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.
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Srinivas R
SR
Chirapu
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
Jonathan N
JN
Bauman
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
Heather
H
Eng
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
Theunis C
TC
Goosen
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA.
Timothy J
TJ
Strelevitz
Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Subhash C
SC
Sinha
Pfizer Global Research & Development, 620 Memorial Drive, Cambridge, MA 02139, USA. Electronic address: robert.l.dow@pfizer.com.
Robert L
RL
Dow
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. Electronic address: mgfinn@gatech.edu.
M G
MG
Finn
D021542:Amino Acids, Neutral / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043182:Carboxylesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D021542:Amino Acids, Neutral; D002219:Carbamates; C013809:5-aminovaleric acid; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase
Carboxylesterase; Cleavable linkers; Drug targeting; Liver targeting