We report on methylsulfamic acid 3-(2-methoxyphenoxy)-2-[[(methylamino)sulfonyl]oxy]propyl ester (1) and its optical isomers [2, S-(-); 3, R-(+)], examples of the sulfamate ester pharmacophore, which have antiarthritic activity in the rat adjuvant-induced arthritis (AA) model and a pharmacological profile suggesting a mechanism distinct from previously reported agents. Compound 1 was synthesized from commercially available 4 in 82% yield, and its optical isomers 2 and 3 were prepared from the optical isomers of 4. In the AA model, 1 showed significant activity against edema and bone destruction at doses as low as 3.16 mg/kg; the S-(-)-isomer (2) was active at 10 mg/kg, while the R-(+)-isomer (3) was inactive at 31.6 mg/kg (the highest dose tested), and compound 4 was inactive at 100 mg/kg. When administered daily at 10 mg/kg PO beginning 18 days prior to adjuvant injection, 1 did not inhibit the generation of the arthritic state but suppressed existing arthritic lesions. Histological analysis revealed that 1 significantly suppressed osteolysis, chondrolysis, synovitis, connective-tissue proliferation, and cellular inflammatory reaction in adjuvant arthritic rats, with no significant effects on serum diagnostic values or weight changes. Compound 1 was inactive in acute inflammation models (carrageenan-induced pleurisy and paw edema), had no analgesic activity, did not block PAF-induced edema or passive anaphylactic response in rats, and had no effect on delayed-type hypersensitivity (DTH) in mice. It did not inhibit cyclooxygenase from sheep seminal vesicles or enzymes of the 5-lipoxygenase pathway in human blood neutrophils, nor did it inhibit carbonic anhydrase, and lacked diuretic or anticonvulsant activity. Summarily, 1 represents a new chemical class (sulfamate esters) of antiarthritic agents with a distinct mechanism of action, and the greater potency of the S-(-)-isomer (2) suggests a specific binding site mediating its effects on edema and bone changes in the AA model.