1346434-72-7

Upstream product

• 1346434-58-9 O-[7-azido-1-(methylsulfonyl)-2-heptyl]-N-[4’-(diethylcarbamoyl)phenyl]carbamate 
• 51207-85-3 4-amino-N,N-diethylbenzamide 
• 1346434-30-7 1-(methylsulfonyl)-7-azido-2-heptanol 
• 1346434-41-0 1-(methanesulfonyl)-7-azido-2-heptyl chloroformate 
• 1346434-63-6 O-[1-(methanesulfonyl)-7-azido-2-heptyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethyl carbamate 
• 86639-52-3 7-ethyl-10-hydroxycamptothecin 

Relevant academic research and scientific papers

Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN-38 with ultralong half-life, low C max, and low glucuronide formation

We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low Cmax, is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

CONTROLLED RELEASE FROM MACROMOLECULAR CONJUGATES

The invention relates to conjugates of macromolecular carriers and drugs comprising linkers that release the drug or a prodrug through rate-controlled beta-elimination, and methods of making and using the conjugates.