Molecular design, synthesis, and antiinflammatory activity of a series of beta-aminoxypropionic acids.
Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.
Macchia
B
B
Istituto di Chimica Farmaceutica, Universita' di Pisa, Italy.
Balsamo
A
A
Lapucci
A
A
Macchia
F
F
Martinelli
A
A
Nencetti
S
S
Orlandini
E
E
Baldacci
M
M
Mengozzi
G
G
Soldani
G
G
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D015195:Drug Design; D005260:Female; D008958:Models, Molecular; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; C015670:2-aminooxypropionic acid; D000409:Alanine