Synthesis physicochemical profile and PAMPA study of new NO-donor edaravone co-drugs.
A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO(x)) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
Barbara
B
Rolando
Andrea
A
Filieri
Konstantin
K
Chegaev
Loretta
L
Lazzarato
Marta
M
Giorgis
Claudio
C
De Nardi
Roberta
R
Fruttero
Sophie
S
Martel
Pierre-Alain
PA
Carrupt
Alberto
A
Gasco
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D000077553:Edaravone; D006801:Humans; D009566:Nitrates / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D009573:Nitrites / Q000378:metabolism; D010539:Permeability; D051381:Rats; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D014665:Vasodilator Agents; D000077553:Edaravone; D000983:Antipyrine