Journal of Medicinal Chemistry p. 1300 - 1307 (1983)
Update date:2022-08-11
Topics:
Brown, Joseph P.
McGarraugh, Geoff V.
Parkinson, Thomas M.
Wingard, Robert E.
Onderdonk, Andrew B.
Sulfasalazine (SASP) consists of salicylic acid azo linked at the 5-position to a pyridine-containing sulfonamide.This drug, currently used in inflammatory bowel disease treatment, is reductively cleaved by anaerobic bacteria in the lower bowel to 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP).Recent reports indicate that 5-ASA is the active therapeutic moiety and that SP is responsible for a variety of adverse clinical side effects.Water-soluble polymer 7, which contains salicylate residues azo linked at the 5-position to an inert polymer backbone, has been synthesized for the side-specific reductive release of 5-ASA in the lower bowel.Preparations of 7 deliver (chemical reduction) >1.96 mmol of 5-ASA/g of polymer.In vitro studies with the polymer in anaerobic rat cecal bacteria demonstrated a reduction rate of approximately 1 μequiv of azo bond h-1 (mL of cecal content)-1.A pharmacokinetic comparison of polymer and SASP showed similar deliveries of 5-ASA and metabolites to the lower bowel, blood and urine of orally dosed rats.Polymer 7 proved more active than SASP or 5-ASA in the guinea pigs ulcerative colitis model.Potential therapeutic advantages of 7 include nonabsorption/nonmetabolism in the small intestine, direct 5-ASA release at the disease site, and nonabsorption/nonmetabolism of the reduction-released carrier polymer.
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