title: The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine.
abstract: To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumors. When administered orally to monkeys, a derivative having the N4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys.
authors.affiliation: Department of Chemistry, Nippon Roche Research Center, Kamakura City, Kanagawa, Japan. nobuo.shimma@roche.com
authors.forename: N
authors.initials: N
authors.lastname: Shimma
authors.forename: I
authors.initials: I
authors.lastname: Umeda
authors.forename: M
authors.initials: M
authors.lastname: Arasaki
authors.forename: C
authors.initials: C
authors.lastname: Murasaki
authors.forename: K
authors.initials: K
authors.lastname: Masubuchi
authors.forename: Y
authors.initials: Y
authors.lastname: Kohchi
authors.forename: M
authors.initials: M
authors.lastname: Miwa
authors.forename: M
authors.initials: M
authors.lastname: Ura
authors.forename: N
authors.initials: N
authors.lastname: Sawada
authors.forename: H
authors.initials: H
authors.lastname: Tahara
authors.forename: I
authors.initials: I
authors.lastname: Kuruma
authors.forename: I
authors.initials: I
authors.lastname: Horii
authors.forename: H
authors.initials: H
authors.lastname: Ishitsuka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D000069287:Capecitabine; D002219:Carbamates / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods / Q000592:standards; D005467:Floxuridine / Q000097:blood / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007422:Intestines / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000592:standards; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D011355:Prodrugs; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; C418208:5'-deoxy-5-fluorocytidine; D002265:Carboxylic Ester Hydrolases; D005472:Fluorouracil