Acetic acid aldose reductase inhibitors bearing a five-membered heterocyclic core with potent topical activity in a visual impairment rat model.
A number of 1,2,4-oxadiazol-5-yl-acetic acids and oxazol-4-yl-acetic acids were synthesized and tested for their ability to inhibit aldose reductase (ALR2). The oxadiazole derivatives, 7c, 7f, 7i, and 8h, 8i, proved to be the most active compounds, exhibiting inhibitory levels in the submicromolar range. In this series, the phenyl group turned out to be the preferred substitution pattern, as its lengthening to a benzyl moiety determined a general reduction of the inhibitory potency. The lead compound, 2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]acetic acid, 7c, showed an excellent in vivo activity, proving to prevent cataract development in severely galactosemic rats when administered as an eye-drop solution in the precorneal region of the animals. Computational studies on the ALR2 inhibitors were performed to rationalize the structure-activity relationships observed and to provide the basis for further structure-guided design of novel ALR2 inhibitors.
La Motta
Concettina
C
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Pisa, Italy. lamotta@farm.unipi.it
Sartini
Stefania
S
Salerno
Silvia
S
Simorini
Francesca
F
Taliani
Sabrina
S
Marini
Anna Maria
AM
Da Settimo
Federico
F
Marinelli
Luciana
L
Limongelli
Vittorio
V
Novellino
Ettore
E
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000287:Administration, Topical; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002386:Cataract / Q000209:etiology / Q000517:prevention & control*; D005693:Galactosemias / Q000150:complications; D008958:Models, Molecular; D009883:Ophthalmic Solutions; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C530305:2-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)acetic acid; D000085:Acetates; D009883:Ophthalmic Solutions; D010069:Oxadiazoles; D010080:Oxazoles; D000449:Aldehyde Reductase