Rapamycin analogs with reduced systemic exposure

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 23; pp. 5340 - 5343
• Main Authors: Wagner, Rolf, Mollison, Karl W., Liu, Luping, Henry, Cynthia L., Rosenberg, Teresa A., Bamaung, Nwe, Tu, Noah, Wiedeman, Paul E., Or, Yatsun, Luly, Jay R., Lane, Benjamin C., Trevillyan, James, Chen, Yung-Wu, Fey, Thomas, Hsieh, Gin, Marsh, Kennan, Nuss, Merrill, Jacobson, Peer B., Wilcox, Denise, Carlson, Richard P., Carter, George W., Djuric, Stevan W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2005; Elsevier
• Subjects: Animals; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacokinetics; Antirheumatic Agents - toxicity; Arthritis, Rheumatoid - diagnostic imaging; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Biological and medical sciences; Immunomodulators; Male; Medical sciences; Pharmacology. Drug treatments; Radiography; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sirolimus - analogs & derivatives; Immunopathology; Rat; Sirolimus; Rodentia; Autoimmune disease; Organic carbamate; Biological activity; Immunomodulator; In vivo; Vertebrata; Chemical modification; Experimental disease; Mammalia; Animal; Immunosuppressive agent; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.06.106

The synthesis and biological activities of highly efficacious rapamycin analogs 3 and 6 in various autoimmune disease models are reported. A shorter plasma half-life of 3 and 6, compared to rapamycin, was measured in rats, and a reduced t 1/2 of 3 versus rapamycin was verified in patients. The synthesis and biological activities of rapamycin ( I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.