title: Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.
abstract: Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.
authors.affiliation: Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Robinson
authors.forename: L A
authors.initials: LA
authors.lastname: Reiter
authors.forename: W E
authors.initials: WE
authors.lastname: Barth
authors.forename: A M
authors.initials: AM
authors.lastname: Campeta
authors.forename: K
authors.initials: K
authors.lastname: Cooper
authors.forename: B J
authors.initials: BJ
authors.lastname: Cronin
authors.forename: R
authors.initials: R
authors.lastname: Destito
authors.forename: K M
authors.initials: KM
authors.lastname: Donahue
authors.forename: F C
authors.initials: FC
authors.lastname: Falkner
authors.forename: E F
authors.initials: EF
authors.lastname: Fiese
authors.forename: D L
authors.initials: DL
authors.lastname: Johnson
authors.forename: A V
authors.initials: AV
authors.lastname: Kuperman
authors.forename: T E
authors.initials: TE
authors.lastname: Liston
authors.forename: D
authors.initials: D
authors.lastname: Malloy
authors.forename: J J
authors.initials: JJ
authors.lastname: Martin
authors.forename: D Y
authors.initials: DY
authors.lastname: Mitchell
authors.forename: F W
authors.initials: FW
authors.lastname: Rusek
authors.forename: S L
authors.initials: SL
authors.lastname: Shamblin
authors.forename: C F
authors.initials: CF
authors.lastname: Wright
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004285:Dogs; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D005650:Fumarates / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008298:Maleates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004987:Ethers; D005650:Fumarates; D007211:Indoles; D008298:Maleates; D011355:Prodrugs; C097761:mono((1-(aminocarbonyl)-6-chloro-5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)-2-thienylmethyl) butenedioate