Synthesis and characterization of new and potent alpha-lipoic acid derivatives.
alpha-Lipoic acid [5-[1,2]-dithiolan-3-yl-pentanoic acid (LA)] is a natural antioxidant and cofactor of several enzymes. It increases the glucose transport activity in skeletal muscles and adipocytes in a non-insulin dependent manner. Therefore, LA is widely used in Type 2 diabetic patients as an oral auxiliary drug. However, large doses of LA (0.8-1.8 gr/day p.o.) are required due to its unfavorable pharmacokinetic parameters. In order to improve these parameters, we synthesized ester and amide LA derivates. Two of these newly synthesized compounds, 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]dithiolan-3yl-pentanoylamino)-propyl]-amide (AN-7) and 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]-dithiolan-3yl-pentanoyloxy)-propyl ester (AN-8) augmented the rate glucose transport in myotubes in culture in the absence or presence of insulin. Their potency was 12-fold higher than that of the parent compound; their maximal stimulatory effect was 1.5-fold higher than that of LA. When tested in vivo in streptozotocin-diabetic C57/Black mice, AN-7 (10 mg/kg/day for 2 weeks, s.c.) reduced blood glucose level by 39% while a higher dose of LA (50 mg/kg/day for 2 weeks, s.c.) lowered it by 30%. These results indicate that AN-7 is more potent than LA in augmenting glucose transport in skeletal muscles and reducing blood glucose in diabetic animals.
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12272, Jerusalem, Israel.
Arie
A
Gruzman
Adel
A
Hidmi
Jehoshua
J
Katzhendler
Abdalla
A
Haj-Yehie
Shlomo
S
Sasson
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004952:Esters / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D013311:Streptozocin; D013329:Structure-Activity Relationship; D008063:Thioctic Acid / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology
D001786:Blood Glucose; D004952:Esters; D013311:Streptozocin; D008063:Thioctic Acid; D005947:Glucose