Synthesis and biological evaluation of menthol-based derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 19; pp. 3361 - 3365
• Main Authors: Ye, Bin, Bauer, Shawn, Buckman, Brad O., Ghannam, Ameen, Griedel, Brian D., Khim, Seock-Kyu, Lee, Wheeseong, Sacchi, Karna L., Shaw, Kenneth J., Liang, Amy, Wu, Qingyu, Zhao, Zuchun
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06.10.2003; Elsevier
• Subjects: Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Drug Evaluation, Preclinical - methods; Medical sciences; Methanol - chemical synthesis; Methanol - pharmacology; Pharmacology. Drug treatments; Plasminogen Activator Inhibitor 1 - metabolism; Rats; Nitro compound; Rat; Combinatorial chemistry; Plasminogen activator inhibitor 1; Structure activity relation; Carboxylic acid; Chemical compound library; Antithrombotic agent; Chemical synthesis; Terpenoid; Ether; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Carboxamide; Benzenic compound; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00686-3

Compound 1 was identified by high throughput screening as a novel PAI-1 inhibitor. Optimization of the B and C-segments of 1 resulted in a series of structurally simplified compounds with improved potency. The synthesis and SAR data of these compounds are presented here. Optimization of the B and C-segments of lead 1 found through HTS led to the identification of a more potent PAI-1 inhibitor 53 with a simplified structure.