Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.
Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).
Van Zandt
Michael C
MC
The Institute for Diabetes Discovery, LLC, 23 Business Park Drive, Branford, Connecticut 06405, USA. michael.vanzandt@ ipd-discovery.com
Jones
Michael L
ML
Gunn
David E
DE
Geraci
Leo S
LS
Jones
J Howard
JH
Sawicki
Diane R
DR
Sredy
Janet
J
Jacot
Jorge L
JL
Dicioccio
A Thomas
AT
Petrova
Tatiana
T
Mitschler
Andre
A
Podjarny
Alberto D
AD
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000818:Animals; D002386:Cataract / Q000188:drug therapy; D002908:Chronic Disease; D018360:Crystallography, X-Ray; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
D007210:Indoleacetic Acids; D013844:Thiazoles; C500848:lidorestat; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase